Oligonucleotides for treatment of angiopoietin like 4 (ANGPTL4) related diseases

ABSTRACT

Provided are compositions comprising an oligonucleotide that targets Angiopoietin-like 4 (ANGPTL4). The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating a metabolic or cardiovascular disorder by providing an oligonucleotide that targets ANGPTL4 to a subject in need thereof.

CROSS-REFERENCE

The present application is a continuation of International PatentApplication No. PCT/US2020/063824, filed Dec. 8, 2020, which claims thebenefit of U.S. Provisional Application No. 62/945,732 filed Dec. 9,2019, each of which is incorporated herein by reference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Sep. 15, 2021, isnamed 54462-712_301_SL.txt and is 4,087,518 bytes in size.

BACKGROUND

Cardiovascular and metabolic disorders are becoming increasinglyabundant, and may affect a wide variety of persons. Improvedtherapeutics are needed for treating these disorders.

SUMMARY

Disclosed herein, in some embodiments, are compositions comprising anoligonucleotide that targets Angiopoietin-like 4 (ANGPTL4) and whenadministered to a subject in an effective amount decreases circulatingtriglycerides, decreases circulating glucose, increases circulatinghigh-density lipoproteins (HDL), or increases insulin sensitivity,wherein the oligonucleotide comprises a small interfering RNA (siRNA)comprising a sense strand and an antisense strand, the antisense strandbeing complementary with no more than 2 mismatches to a portion of anucleic acid having the nucleoside sequence of SEQ ID NO: 13935, andeach strand having 12 to 30 nucleotides. In some embodiments, thetriglycerides, total cholesterol, or glucose is decreased by about 10%or more, or the HDL or insulin sensitivity is increased by about 10% ormore, as compared to prior to administration. In some embodiments, theantisense strand is complementary with no more than 2 mismatches to aportion of a nucleic acid having the nucleoside sequence of SEQ ID NO:13936. In some embodiments, the antisense strand comprises a nucleosidesequence at least 85% identical to an antisense strand sequence of ansiRNA in Table 4. In some embodiments, the antisense strand comprisesthe nucleoside sequence of an antisense strand sequence of an siRNA inTable 4, or an antisense strand sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the antisense strand comprises the nucleoside sequence of an antisensestrand sequence of an siRNA in Table 4. In some embodiments, the sensestrand comprises a nucleoside sequence at least 85% identical to thesense strand sequence of the siRNA in Table 4. In some embodiments, thesense strand comprises the nucleoside sequence of the sense strandsequence of the siRNA in Table 4, or a sense strand sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises the nucleoside sequence of thesense strand sequence of the siRNA in Table 4. In some embodiments, theantisense strand comprises a nucleoside sequence at least 85% identicalto SEQ ID NO: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144,2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425,2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005,3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284,3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696. Insome embodiments, the antisense strand comprises the nucleoside sequenceof SEQ ID NO: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144,2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425,2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005,3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284,3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696, oran antisense strand sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, theantisense strand comprises the nucleoside sequence of SEQ ID NO: 1886,1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180,2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613,2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020,3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434,3435, 3443, 3451, 3465, 3556, 3694, or 3696. In some embodiments, thesense strand comprises a nucleoside sequence at least 85% identical toSEQ ID NO: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326,332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876,1001, 1133, 1134, 1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172,1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589,1597, 1611, 1702, 1840, or 1842. In some embodiments, the sense strandcomprises the nucleoside sequence of SEQ ID NO: 32, 33, 35, 36, 121,280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519, 565,570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1149,1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348,1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840, or1842, or a sense strand sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, the sensestrand comprises the nucleoside sequence of SEQ ID NO: 32, 33, 35, 36,121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519,565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137,1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338,1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840,or 1842. In some embodiments, the antisense strand comprises anucleoside sequence at least 85% identical to any of SEQ ID NOS:13978-13981. In some embodiments, the antisense strand comprises thenucleoside sequence of any of SEQ ID NOS: 13978-13981, or an antisensestrand sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the antisense strandcomprises the nucleoside sequence of any of SEQ ID NOS: 13978-13981. Insome embodiments, the sense strand comprises a nucleoside sequence atleast 85% identical to any of SEQ ID NOS: 13970-13973. In someembodiments, the sense strand comprises the nucleoside sequence of anyof SEQ ID NOS: 13970-13973, or a sense strand sequence thereof having 1or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises the nucleoside sequence of anyof SEQ ID NOS: 13970-13973. In some embodiments, the oligonucleotidecomprises a modified internucleoside linkage. In some embodiments, themodified internucleoside linkage comprises alkylphosphonate,phosphorothioate, methylphosphonate, phosphorodithioate,alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphatetriester, acetamidate, or carboxymethyl ester, or a combination thereof.In some embodiments, the modified internucleoside linkage comprises aphosphorothioate linkage. In some embodiments, the sense strandcomprises 2-6 modified internucleoside linkages. In some embodiments,the antisense strand comprises 2-6 modified internucleoside linkages. Insome embodiments, the oligonucleotide comprises a modified nucleoside.In some embodiments, the modified nucleoside comprise a locked nucleicacid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA),a 2′,4′ constrained ethyl, 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl,2′-O-allyl, 2′-fluoro, 2′-deoxy, a 2′ 0 methyl nucleoside,2′-deoxyfluoro nucleoside, 2′-O—N-methylacetamido (2′-O-NMA) nucleoside,a 2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleoside,2′-O-aminopropyl (2′-O-AP) nucleoside, 2′ ara-F, or a combinationthereof. In some embodiments, the modified nucleoside comprises a 2′fluoro modified nucleoside. In some embodiments, the modified nucleosidecomprises a 2′ 0 methyl modified nucleoside. In some embodiments, thesense strand or antisense strand comprises 15-21 modified nucleosides.In some embodiments, the sense strand or the antisense strand comprisesa 3′ overhang of at least 2 nucleosides. In some embodiments, theoligonucleotide comprises a GalNAc ligand attached at a 3′ or 5′terminus of the sense strand. In some embodiments, the oligonucleotidecomprises a GalNAc ligand attached at a 3′ or 5′ terminus of theantisense strand In some embodiments, the sense strand comprisesmodification pattern 1S: 5′ NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′ (SEQID NO: 13954), modification pattern 2S: 5′nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13955), modificationpattern 3S: 5′ nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13956),modification pattern 4S: 5′ NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3′(SEQ ID NO: 13957), modification pattern 5S:5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3′ (SEQ ID NO: 13958); modificationpattern 6S: 5′ NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn 3′ (SEQ ID NO:13959); wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′O-methyl modified nucleoside, “s” is a phosphorothioate linkage, and Ncomprises a nucleoside. In some embodiments, the antisense strandcomprises modification pattern 1AS: 5′nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13960), modificationpattern 2AS: 5′ nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13961),modification pattern 3AS: 5′ nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′ (SEQ IDNO: 13962), modification pattern 4AS: 5′ nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn3′ (SEQ ID NO: 13963), modification pattern 5AS: 5′nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn 3′ (SEQ ID NO: 13964), modificationpattern 6AS: 5′ nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn 3′ (SEQ ID NO:13965), modification pattern 7AS: 5′ nsNfsnNfnNfnNfNfnnnnNfnNfnnnsnsn 3′(SEQ ID NO: 13966), modification pattern 8AS: 5′nsNfsnnnnnnnnnnnNfnnnnsnsn 3′ (SEQ ID NO: 13967), or modificationpattern 9AS: 5′ nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn 3′ (SEQ ID NO: 13968);wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methylmodified nucleoside, and “s” is a phosphorothioate linkage. In someembodiments, the composition is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier. In some embodiments, thepharmaceutically acceptable carrier comprises water, a buffer, or asaline solution.

Disclosed herein, are methods of treating a metabolic or cardiovasculardisorder in a subject in need thereof, the method comprisingadministering to the subject an effective amount of a compositioncomprising an oligonucleotide that targets ANGPTL4, wherein theoligonucleotide comprises a small interfering RNA (siRNA) comprising asense strand and an antisense strand, the antisense strand beingcomplementary with no more than 2 mismatches to a portion of a nucleicacid having the nucleoside sequence of SEQ ID NO: 13936, and each strandhaving 12 to 30 nucleotides. In some embodiments, the disorder compriseshyperlipidemia, hypertriglyceridemia, pancreatitis, familialchylomicronemia syndrome, diabetes, type 2 diabetes, heart disease, amyocardial infarction, angina pectoris, or atherosclerosis. In someembodiments, the effective amount of the composition decreases atriglyceride measurement, decreases a cholesterol measurement, decreasesa glucose measurement, increases an HDL measurement, or increases aninsulin sensitivity measurement in the subject by about 10% or more,relative to a baseline measurement. In some embodiments, the antisensestrand is complementary with no more than 2 mismatches to a portion of anucleic acid having the nucleoside sequence of SEQ ID NO: 13935. In someembodiments, the antisense strand comprises a nucleoside sequence atleast 85% identical to SEQ ID NO: 1886, 1887, 1889, 1890, 1975, 2134,2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373,2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988,2991, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139,3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556,3694, or 3696. In some embodiments, the antisense strand comprises thenucleoside sequence of SEQ ID NO: 1886, 1887, 1889, 1890, 1975, 2134,2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373,2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988,2991, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139,3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556,3694, or 3696, or an antisense strand sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the antisense strand comprises the nucleoside sequence of SEQ ID NO:1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177,2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494,2613, 2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011, 3019,3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418,3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696. In some embodiments,the sense strand comprises a nucleoside sequence at least 85% identicalto SEQ ID NO: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323,326, 332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834,876, 1001, 1133, 1134, 1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171,1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581,1589, 1597, 1611, 1702, 1840, or 1842. In some embodiments, the sensestrand comprises the nucleoside sequence of SEQ ID NO: 32, 33, 35, 36,121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519,565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137,1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338,1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840,or 1842, or a sense strand sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, the sensestrand comprises the nucleoside sequence of SEQ ID NO: 32, 33, 35, 36,121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519,565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137,1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338,1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840,or 1842. In some embodiments, the antisense strand comprises anucleoside sequence at least 85% identical to any of SEQ ID NOS:13978-13981. In some embodiments, the antisense strand comprises thenucleoside sequence of any of SEQ ID NOS: 13978-13981, or an antisensestrand sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the antisense strandcomprises the nucleoside sequence of any of SEQ ID NOS: 13978-13981. Insome embodiments, the sense strand comprises a nucleoside sequence atleast 85% identical to any of SEQ ID NOS: 13970-13973. In someembodiments, the sense strand comprises the nucleoside sequence of anyof SEQ ID NOS: 13970-13973, or a sense strand sequence thereof having 1or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises the nucleoside sequence of anyof SEQ ID NOS: 13970-13973. In some embodiments, the oligonucleotidecomprises a modified internucleoside linkage comprising:alkylphosphonate, phosphorothioate, methylphosphonate,phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate,carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or acombination thereof. In some embodiments, the oligonucleotide comprisesa modified nucleoside comprising: a locked nucleic acid (LNA), hexitolnucleic acid (HLA), cyclohexene nucleic acid (CeNA), a 2′,4′ constrainedethyl, 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-O-allyl, 2′-fluoro,2′-deoxy, a 2′ 0 methyl nucleoside, 2′-deoxyfluoro nucleoside,2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl(2′-O-AP) nucleoside, 2′ ara-F, or a combination thereof. In someembodiments, the sense strand or the antisense strand comprises a 3′overhang of at least 2 nucleosides. In some embodiments, theoligonucleotide comprises a GalNAc ligand attached at a 3′ or 5′terminus of the sense strand. In some embodiments, the oligonucleotidecomprises a GalNAc ligand attached at a 3′ or 5′ terminus of theantisense strand In some embodiments, the sense strand comprisesmodification pattern 1S: 5′ NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′ (SEQID NO: 13954), modification pattern 2S: 5′nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13955), modificationpattern 3S: 5′ nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13956),modification pattern 4S: 5′ NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3′(SEQ ID NO: 13957), modification pattern 5S:5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3′ (SEQ ID NO: 13958); modificationpattern 6S: 5′ NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn 3′ (SEQ ID NO:13959); wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′O-methyl modified nucleoside, “s” is a phosphorothioate linkage, and Ncomprises a nucleoside. In some embodiments, the antisense strandcomprises modification pattern 1AS: 5′nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13960), modificationpattern 2AS: 5′ nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13961),modification pattern 3AS: 5′ nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′ (SEQ IDNO: 13962), modification pattern 4AS: 5′ nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn3′ (SEQ ID NO: 13963), modification pattern 5AS: 5′nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn 3′ (SEQ ID NO: 13964), modificationpattern 6AS: 5′ nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn 3′ (SEQ ID NO:13965), modification pattern 7AS: 5′ nsNfsnNfnNfnNfNfnnnnNfnNfnnnsnsn 3′(SEQ ID NO: 13966), modification pattern 8AS: 5′nsNfsnnnnnnnnnnnNfnnnnnsnsn 3′ (SEQ ID NO: 13967), or modificationpattern 9AS: 5′ nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn 3′ (SEQ ID NO: 13968);wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methylmodified nucleoside, and “s” is a phosphorothioate linkage.

Disclosed herein are compositions comprising an oligonucleotide thattargets Angiopoietin-like 4 (ANGPTL4) and when administered to a subjectin an effective amount decreases circulating triglycerides. In someembodiments, the triglycerides are decreased by about 10% or more, ascompared to prior to administration. Also disclosed herein arecompositions comprising an oligonucleotide that targets ANGPTL4 and whenadministered to a subject in an effective amount decreases circulatingtotal cholesterol. In some embodiments, the total cholesterol isdecreased by about 10% or more, as compared to prior to administration.Also disclosed herein are compositions comprising an oligonucleotidethat targets ANGPTL4 and when administered to a subject in an effectiveamount increases circulating high-density lipoproteins (HDL). In someembodiments, the HDL are increased by about 10% or more, as compared toprior to administration. Also disclosed herein are compositionscomprising an oligonucleotide that targets ANGPTL4 and when administeredto a subject in an effective amount decreases circulating glucose. Insome embodiments, the glucose is decreased by about 10% or more, ascompared to prior to administration. Also disclosed herein arecompositions comprising an oligonucleotide that targets ANGPTL4 and whenadministered to a subject in an effective amount increases insulinsensitivity. In some embodiments, the insulin sensitivity is increasedby about 10% or more, as compared to prior to administration. In someembodiments, the oligonucleotide comprises a small interfering RNA(siRNA) comprising a sense strand and an antisense strand. In someembodiments, the sense strand is 14-30 nucleosides in length. In someembodiments, the antisense strand is 14-30 nucleosides in length. Alsodisclosed herein are compositions comprising an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,each strand is independently about 14-30 nucleosides in length, and atleast one of the sense strand and the antisense strand comprises anucleoside sequence comprising about 14-30 contiguous nucleosides of SEQID NO: 13935. Also disclosed herein are compositions comprising anoligonucleotide that inhibits the expression of ANGPTL4, wherein theoligonucleotide comprises an siRNA comprising a sense strand and anantisense strand, each strand is independently about 14-30 nucleosidesin length, and at least one of the sense strand and the antisense strandcomprises a nucleoside sequence comprising about 14-30 contiguousnucleosides of SEQ ID NO: 13936. In some embodiments, the sense strandand the antisense strand form a double-stranded RNA duplex. In someembodiments, the first base pair of the double-stranded RNA duplex is anAU base pair. In some embodiments, the sense strand comprises anucleoside sequence comprising or consisting of the sequence of any oneof SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises a nucleoside sequence comprisingor consisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977. In some embodiments, the sense strand further comprises a3′ overhang comprising 1, 2, or more nucleosides. In some embodiments,the antisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985. In some embodiments, the antisense strand further comprisesa 3′ overhang comprising 1, 2, or more nucleosides. In some embodiments,the siRNA binds with a 19mer in a human ANGPTL4 mRNA. In someembodiments, the siRNA binds with a 17mer in a non-human primate ANGPTL4mRNA. In some embodiments, the siRNA binds with a 19mer in a humanANGPTL4 mRNA. In some embodiments, the siRNA binds with a human ANGPTL4mRNA and less than or equal to 20 human off-targets, with no more than 2mismatches in the antisense strand. In some embodiments, siRNA bindswith a human ANGPTL4 mRNA target site that does not harbor an SNP, witha minor allele frequency (MAF) greater or equal to 1% (pos. 2-18). Insome embodiments, the sense strand comprises the nucleoside sequence ofany one of SEQ ID NOs: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63,64, 79, 80, 84, 111, 112, 116, 117, 118, 119, 120, 121, 125, 126, 127,128, 129, 149, 150, 152, 153, 154, 157, 158, 159, 161, 164, 165, 166,167, 168, 169, 172, 174, 175, 177, 196, 198, 199, 210, 211, 212, 214,215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245,246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272,274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326,328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349,350, 352, 353, 356, 377, 380, 382, 386, 388, 391, 392, 393, 394, 397,398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421,422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506,509, 517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612,616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676,677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834,841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868,871, 872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911,912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968,1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052,1053, 1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133,1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158,1161, 1162, 1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184,1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347,1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416,1417, 1418, 1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519,1523, 1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581,1589, 1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613,1614, 1617, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745,1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798,1799, 1800, 1801, 1802, or 1803, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the antisense strand comprises the nucleoside sequence ofany one of SEQ ID NOs: 1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912,1913, 1915, 1916, 1917, 1918, 1933, 1934, 1938, 1965, 1966, 1970, 1971,1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006,2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023,2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066, 2068, 2069,2070, 2071, 2072, 2073, 2075, 2076, 2077, 2082, 2084, 2085, 2094, 2095,2099, 2100, 2104, 2106, 2107, 2108, 2109, 2114, 2115, 2116, 2117, 2119,2120, 2125, 2126, 2128, 2134, 2136, 2143, 2144, 2145, 2146, 2147, 2153,2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188,2189, 2191, 2192, 2193, 2196, 2201, 2203, 2204, 2206, 2207, 2210, 2231,2234, 2236, 2240, 2242, 2245, 2246, 2247, 2248, 2251, 2252, 2253, 2256,2258, 2259, 2265, 2266, 2267, 2268, 2269, 2271, 2273, 2274, 2275, 2276,2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285, 2289, 2335, 2338,2360, 2363, 2371, 2373, 2374, 2419, 2424, 2425, 2426, 2443, 2461, 2462,2464, 2465, 2466, 2470, 2471, 2474, 2477, 2489, 2491, 2494, 2497, 2507,2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533, 2535, 2536, 2537, 2538,2540, 2541, 2543, 2546, 2549, 2684, 2688, 2695, 2696, 2697, 2698, 2704,2705, 2706, 2707, 2708, 2710, 2711, 2713, 2720, 2722, 2725, 2726, 2730,2741, 2742, 2744, 2746, 2747, 2748, 2751, 2754, 2756, 2761, 2765, 2766,2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774, 2775, 2776, 2779, 2799,2822, 2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882, 2886, 2891,2906, 2907, 2908, 2909, 2911, 2912, 2918, 2966, 2976, 2978, 2980, 2981,2987, 2988, 2990, 2991, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011,3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029, 3035, 3036,3038, 3102, 3103, 3106, 3107, 3113, 3130, 3139, 3164, 3169, 3192, 3197,3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267, 3268, 3269,3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341, 3342, 3343, 3347, 3348,3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425, 3426, 3434,3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458, 3459, 3460, 3464, 3465,3467, 3468, 3471, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595, 3596,3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642,3652, 3653, 3654, 3655, 3656, or 3657, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions.In some embodiments, the sense strand comprises the nucleoside sequenceof any one of SEQ ID NO: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63,64, 79, 80, 84, 111, 112, 116, 117, 118, 119, 120, 121, 125, 126, 127,128, 129, 149, 150, 152, 153, 154, 157, 158, 159, 161, 164, 165, 166,167, 168, 169, 172, 174, 175, 177, 196, 198, 199, 210, 211, 212, 214,215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245,246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272,274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326,328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349,350, 352, 353, 356, 377, 380, 382, 386, 388, 391, 392, 393, 394, 397,398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421,422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506,509, 517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612,616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676,677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834,841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868,871, 872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911,912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968,1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052,1053, 1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133,1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158,1161, 1162, 1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184,1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347,1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416,1417, 1418, 1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519,1523, 1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581,1589, 1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613,1614, 1617, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745,1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798,1799, 1800, 1801, 1802, or 1803. In some embodiments, the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 1886,1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918,1933, 1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979,1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007, 2008, 2011, 2012, 2013,2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050,2052, 2053, 2064, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075,2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107,2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134,2136, 2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180,2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196,2201, 2203, 2204, 2206, 2207, 2210, 2231, 2234, 2236, 2240, 2242, 2245,2246, 2247, 2248, 2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267,2268, 2269, 2271, 2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281,2282, 2283, 2284, 2285, 2289, 2335, 2338, 2360, 2363, 2371, 2373, 2374,2419, 2424, 2425, 2426, 2443, 2461, 2462, 2464, 2465, 2466, 2470, 2471,2474, 2477, 2489, 2491, 2494, 2497, 2507, 2526, 2527, 2528, 2529, 2530,2531, 2532, 2533, 2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546, 2549,2684, 2688, 2695, 2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710,2711, 2713, 2720, 2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746, 2747,2748, 2751, 2754, 2756, 2761, 2765, 2766, 2767, 2768, 2769, 2770, 2771,2772, 2773, 2774, 2775, 2776, 2779, 2799, 2822, 2855, 2856, 2859, 2860,2863, 2864, 2865, 2867, 2882, 2886, 2891, 2906, 2907, 2908, 2909, 2911,2912, 2918, 2966, 2976, 2978, 2980, 2981, 2987, 2988, 2990, 2991, 3001,3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018,3019, 3020, 3025, 3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106, 3107,3113, 3130, 3139, 3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205,3206, 3232, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284,3302, 3331, 3341, 3342, 3343, 3347, 3348, 3373, 3377, 3392, 3410, 3415,3417, 3418, 3419, 3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455,3456, 3457, 3458, 3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 3553,3555, 3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605,3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656,or 3657. In some embodiments, the sense strand comprises the nucleosidesequence of any one of SEQ ID NOs: 33, 34, 35, 36, 56, 121, 272, 280,282, 289, 290, 291, 292, 293, 321, 323, 326, 328, 329, 330, 331, 332,333, 334, 335, 337, 338, 339, 342, 347, 349, 411, 412, 430, 431, 435,481, 484, 509, 517, 519, 520, 565, 620, 635, 637, 640, 830, 834, 841,842, 843, 844, 850, 871, 872, 876, 887, 888, 894, 897, 902, 945, 1001,1002, 1005, 1037, 1133, 1134, 1137, 1149, 1151, 1153, 1154, 1155, 1157,1158, 1161, 1162, 1164, 1165, 1166, 1171, 1172, 1248, 1249, 1315, 1338,1343, 1347, 1348, 1429, 1430, 1570, 1571, 1572, 1610, 1611, 1617, 1780,1784, or 1787, or a nucleic acid sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the antisense strand comprises the nucleoside sequence of any one of SEQID NOs: 1887, 1888, 1889, 1890, 1910, 1975, 2126, 2134, 2136, 2143,2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186,2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284,2285, 2289, 2335, 2338, 2363, 2371, 2373, 2374, 2419, 2474, 2489, 2491,2494, 2684, 2688, 2695, 2696, 2697, 2698, 2704, 2725, 2726, 2730, 2741,2742, 2748, 2751, 2756, 2799, 2855, 2856, 2859, 2891, 2987, 2988, 2991,3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020,3025, 3026, 3102, 3103, 3169, 3192, 3197, 3201, 3202, 3283, 3284, 3424,3425, 3426, 3464, 3465, 3471, 3634, 3638, or 3641, or a nucleic acidsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions. In some embodiments, the sense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 32, 33, 34, 35, 36, 56,57, 58, 59, 61, 62, 63, 64, 79, 80, 112, 116, 117, 118, 119, 120, 125,126, 127, 128, 129, 149, 150, 152, 153, 157, 158, 159, 161, 164, 165,166, 167, 168, 169, 172, 174, 175, 196, 199, 211, 212, 214, 215, 216,217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245, 246, 250,252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280,289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330,331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353,356, 380, 382, 386, 388, 391, 392, 393, 394, 397, 398, 399, 402, 404,405, 411, 412, 413, 414, 415, 420, 421, 422, 423, 424, 425, 426, 427,428, 429, 430, 431, 435, 484, 517, 519, 520, 565, 570, 571, 572, 607,608, 610, 611, 612, 616, 617, 620, 635, 637, 640, 672, 673, 674, 675,676, 677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830,841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 866, 868, 871,872, 876, 887, 888, 890, 892, 893, 894, 902, 911, 912, 913, 914, 915,916, 917, 918, 919, 920, 921, 922, 945, 1001, 1002, 1005, 1006, 1009,1010, 1011, 1013, 1028, 1032, 1052, 1053, 1054, 1055, 1057, 1058, 1112,1122, 1124, 1126, 1127, 1133, 1134, 1147, 1148, 1149, 1151, 1153, 1154,1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1175, 1182, 1184, 1252,1253, 1259, 1276, 1285, 1310, 1315, 1343, 1347, 1348, 1349, 1350, 1351,1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430, 1448, 1519,1523, 1556, 1561, 1563, 1564, 1565, 1571, 1572, 1580, 1581, 1589, 1597,1601, 1602, 1603, 1604, 1605, 1606, 1611, 1613, 1614, 1693, 1699, 1701,1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754,1755, 1779, 1780, 1784, 1788, 1798, 1799, 1801, 1802, or 1803, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the antisense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 1886, 1887,1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933,1934, 1966, 1970, 1971, 1972, 1973, 1974, 1979, 1980, 1981, 1982, 1983,2003, 2004, 2006, 2007, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021,2022, 2023, 2026, 2028, 2029, 2050, 2053, 2065, 2066, 2068, 2069, 2070,2071, 2072, 2073, 2075, 2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099,2100, 2104, 2106, 2107, 2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120,2125, 2126, 2128, 2134, 2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175,2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191,2192, 2193, 2196, 2201, 2203, 2204, 2206, 2207, 2210, 2234, 2236, 2240,2242, 2245, 2246, 2247, 2248, 2251, 2252, 2253, 2256, 2258, 2259, 2265,2266, 2267, 2268, 2269, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281,2282, 2283, 2284, 2285, 2289, 2338, 2371, 2373, 2374, 2419, 2424, 2425,2426, 2461, 2462, 2464, 2465, 2466, 2470, 2471, 2474, 2489, 2491, 2494,2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533, 2535, 2536, 2537, 2538,2540, 2541, 2543, 2546, 2549, 2684, 2695, 2696, 2697, 2698, 2704, 2705,2706, 2707, 2708, 2710, 2711, 2720, 2722, 2725, 2726, 2730, 2741, 2742,2744, 2746, 2747, 2748, 2756, 2765, 2766, 2767, 2768, 2769, 2770, 2771,2772, 2773, 2774, 2775, 2776, 2799, 2855, 2856, 2859, 2860, 2863, 2864,2865, 2867, 2882, 2886, 2906, 2907, 2908, 2909, 2911, 2912, 2966, 2976,2978, 2980, 2981, 2987, 2988, 3001, 3002, 3003, 3005, 3007, 3008, 3009,3011, 3012, 3015, 3016, 3018, 3019, 3020, 3029, 3036, 3038, 3106, 3107,3113, 3130, 3139, 3164, 3169, 3197, 3201, 3202, 3203, 3204, 3205, 3259,3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3373, 3377,3410, 3415, 3417, 3418, 3419, 3425, 3426, 3434, 3435, 3443, 3451, 3455,3456, 3457, 3458, 3459, 3460, 3465, 3467, 3468, 3547, 3553, 3555, 3556,3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609,3633, 3634, 3638, 3642, 3652, 3653, 3655, 3656, or 3657, or a nucleicacid sequence thereof having 1 or 2 nucleoside substitutions, additions,or deletions. In some embodiments, the sense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 33, 34, 35, 36, 56, 272,280, 289, 290, 291, 292, 293, 321, 323, 326, 328, 329, 330, 331, 332,333, 334, 335, 337, 338, 339, 342, 347, 349, 411, 412, 430, 431, 435,484, 517, 519, 520, 565, 620, 635, 637, 640, 830, 841, 842, 843, 844,850, 871, 872, 876, 887, 888, 894, 902, 945, 1001, 1002, 1005, 1133,1134, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165,1166, 1315, 1343, 1347, 1348, 1429, 1430, 1571, 1572, 1611, 1780, or1784, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, theantisense strand comprises the nucleoside sequence of any one of SEQ IDNOs: 1887, 1888, 1889, 1890, 1910, 2126, 2134, 2143, 2144, 2145, 2146,2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189,2191, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2338,2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494, 2684, 2695, 2696, 2697,2698, 2704, 2725, 2726, 2730, 2741, 2742, 2748, 2756, 2799, 2855, 2856,2859, 2987, 2988, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016,3018, 3019, 3020, 3169, 3197, 3201, 3202, 3283, 3284, 3425, 3426, 3465,3634, or 3638, or a nucleic acid sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the antisense strand comprises a seed region that is not identical to aseed region of a human miRNA. In some embodiments, the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 32, 36, 56,57, 58, 61, 62, 79, 80, 117, 119, 125, 126, 128, 149, 152, 157, 158,159, 161, 165, 166, 167, 168, 169, 174, 196, 211, 212, 217, 218, 219,230, 231, 245, 246, 253, 260, 261, 262, 271, 272, 280, 289, 291, 292,293, 304, 321, 323, 325, 326, 328, 330, 331, 332, 333, 334, 337, 338,342, 347, 349, 352, 353, 356, 380, 382, 386, 388, 391, 392, 394, 399,413, 414, 415, 422, 423, 424, 425, 426, 435, 517, 519, 520, 565, 571,607, 608, 612, 617, 620, 635, 640, 672, 673, 674, 675, 678, 679, 681,683, 684, 687, 692, 842, 843, 850, 851, 854, 866, 868, 876, 892, 893,902, 911, 912, 913, 914, 916, 919, 945, 1001, 1002, 1006, 1010, 1028,1052, 1053, 1054, 1055, 1057, 1112, 1124, 1127, 1147, 1149, 1151, 1153,1155, 1157, 1164, 1175, 1182, 1184, 1259, 1276, 1285, 1315, 1343, 1349,1350, 1351, 1405, 1407, 1413, 1415, 1418, 1564, 1571, 1581, 1589, 1597,1601, 1602, 1603, 1604, 1605, 1606, 1613, 1614, 1693, 1701, 1722, 1740,1745, 1751, 1755, 1801, 1802, or 1803, or 3638, or a nucleic acidsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions. In some embodiments, the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1886, 1890, 1910, 1911,1912, 1915, 1916, 1933, 1934, 1971, 1973, 1979, 1980, 1982, 2003, 2006,2011, 2012, 2013, 2015, 2019, 2020, 2021, 2022, 2023, 2028, 2050, 2065,2066, 2071, 2072, 2073, 2084, 2085, 2099, 2100, 2107, 2114, 2115, 2116,2125, 2126, 2134, 2143, 2145, 2146, 2147, 2158, 2175, 2177, 2179, 2180,2182, 2184, 2185, 2186, 2187, 2188, 2191, 2192, 2196, 2201, 2203, 2206,2207, 2210, 2234, 2236, 2240, 2242, 2245, 2246, 2248, 2253, 2267, 2268,2269, 2276, 2277, 2278, 2279, 2280, 2289, 2371, 2373, 2374, 2419, 2425,2461, 2462, 2466, 2471, 2474, 2489, 2494, 2526, 2527, 2528, 2529, 2532,2533, 2535, 2537, 2538, 2541, 2546, 2696, 2697, 2704, 2705, 2708, 2720,2722, 2730, 2746, 2747, 2756, 2765, 2766, 2767, 2768, 2770, 2773, 2799,2855, 2856, 2860, 2864, 2882, 2906, 2907, 2908, 2909, 2911, 2966, 2978,2981, 3001, 3003, 3005, 3007, 3009, 3011, 3018, 3029, 3036, 3038, 3113,3130, 3139, 3169, 3197, 3203, 3204, 3205, 3259, 3261, 3267, 3269, 3272,3418, 3425, 3435, 3443, 3451, 3455, 3456, 3457, 3458, 3459, 3460, 3467,3468, 3547, 3555, 3576, 3594, 3599, 3605, 3609, 3655, 3656, or 3657, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the sense strand comprisesthe nucleoside sequence of any one of SEQ ID 36, 56, 272, 280, 289, 291,292, 293, 321, 323, 326, 328, 330, 331, 332, 333, 334, 337, 338, 342,347, 349, 435, 517, 519, 520, 565, 620, 635, 640, 842, 843, 850, 876,902, 945, 1001, 1002, 1149, 1151, 1153, 1155, 1157, 1164, 1315, 1343, or1571, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, theantisense strand comprises the nucleoside sequence of any one of SEQ ID1890, 1910, 2126, 2134, 2143, 2145, 2146, 2147, 2175, 2177, 2180, 2182,2184, 2185, 2186, 2187, 2188, 2191, 2192, 2196, 2201, 2203, 2289, 2371,2373, 2374, 2419, 2474, 2489, 2494, 2696, 2697, 2704, 2730, 2756, 2799,2855, 2856, 3003, 3005, 3007, 3009, 3011, 3018, 3169, 3197, or 3425, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the sense strand comprisesa seed region that is not identical to a seed region of a human miRNA.In some embodiments, the sense strand comprises the nucleoside sequenceof any one of SEQ ID NOs: 32, 36, 56, 58, 61, 62, 80, 117, 119, 126,152, 154, 157, 158, 159, 161, 166, 169, 174, 177, 196, 211, 212, 217,218, 230, 231, 245, 253, 260, 261, 271, 272, 280, 289, 293, 304, 328,330, 331, 332, 333, 334, 337, 342, 347, 349, 353, 356, 386, 388, 391,392, 394, 414, 415, 422, 423, 424, 426, 435, 520, 571, 608, 612, 617,653, 672, 678, 679, 681, 683, 692, 842, 843, 851, 854, 859, 876, 892,900, 913, 914, 919, 968, 1001, 1002, 1054, 1057, 1064, 1112, 1124, 1157,1164, 1182, 1184, 1248, 1259, 1343, 1351, 1352, 1415, 1418, 1564, 1581,1602, 1614, 1693, 1701, 1722, 1740, 1751, 1755, or 1787, or a nucleicacid sequence thereof having 1 or 2 nucleoside substitutions, additions,or deletions. In some embodiments, the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1886, 1890, 1910, 1912,1915, 1916, 1934, 1971, 1973, 1980, 2006, 2008, 2011, 2012, 2013, 2015,2020, 2023, 2028, 2031, 2050, 2065, 2066, 2071, 2072, 2084, 2085, 2099,2107, 2114, 2115, 2125, 2126, 2134, 2143, 2147, 2158, 2182, 2184, 2185,2186, 2187, 2188, 2191, 2196, 2201, 2203, 2207, 2210, 2240, 2242, 2245,2246, 2248, 2268, 2269, 2276, 2277, 2278, 2280, 2289, 2374, 2425, 2462,2466, 2471, 2507, 2526, 2532, 2533, 2535, 2537, 2546, 2696, 2697, 2705,2708, 2713, 2730, 2746, 2754, 2767, 2768, 2773, 2822, 2855, 2856, 2908,2911, 2918, 2966, 2978, 3011, 3018, 3036, 3038, 3102, 3113, 3197, 3205,3206, 3269, 3272, 3418, 3435, 3456, 3468, 3547, 3555, 3576, 3594, 3605,3609, or 3641, or a nucleic acid sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the sense strand comprises the nucleoside sequence of any one of SEQ IDNOs: 36, 56, 272, 280, 289, 293, 328, 330, 331, 332, 333, 334, 337, 342,347, 349, 435, 520, 842, 843, 876, 1001, 1002, 1157, 1164, or 1343, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the antisense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 1890, 1910,2126, 2134, 2143, 2147, 2182, 2184, 2185, 2186, 2187, 2188, 2191, 2196,2201, 2203, 2289, 2374, 2696, 2697, 2730, 2855, 2856, 3011, 3018, or3197, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, the sensestrand and/or the antisense strand further comprise a 3′ overhangcomprising 1, 2, or more nucleosides. In some embodiments, the 3′overhang comprises 2 nucleosides. In some embodiments, (i) theoligonucleotide comprises a modification comprising a modifiednucleoside and/or a modified internucleoside linkage, and/or (ii) thecomposition comprises a pharmaceutically acceptable carrier. In someembodiments, the oligonucleotide comprises a modification comprising amodified nucleoside and/or a modified internucleoside linkage. In someembodiments, the oligonucleotide comprises a modified internucleosidelinkage. In some embodiments, the modified internucleoside linkagecomprises alkylphosphonate, phosphorothioate, methylphosphonate,phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate,carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or acombination thereof. In some embodiments, the modified internucleosidelinkage comprises one or more phosphorothioate linkages. In someembodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleosidelinkages. In some embodiments, the oligonucleotide comprises 2 or moremodified internucleoside linkages, 3 or more modified internucleosidelinkages, 4 or more modified internucleoside linkages, 5 or moremodified internucleoside linkages, 6 or more modified internucleosidelinkages, 7 or more modified internucleoside linkages, 8 or moremodified internucleoside linkages, 9 or more modified internucleosidelinkages, 10 or more modified internucleoside linkages, 11 or moremodified internucleoside linkages, 12 or more modified internucleosidelinkages, 13 or more modified internucleoside linkages, 14 or moremodified internucleoside linkages, 15 or more modified internucleosidelinkages, 16 or more modified internucleoside linkages, 17 or moremodified internucleoside linkages, 18 or more modified internucleosidelinkages, 19 or more modified internucleoside linkages, or 20 or moremodified internucleoside linkages. In some embodiments, theoligonucleotide comprises the modified nucleoside. In some embodiments,the modified nucleoside comprises a locked nucleic acid (LNA), hexitolnucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2′-methoxyethyl,2′-O-alkyl, 2′-O-allyl, 2′-O-allyl, 2′-fluoro, or 2′-deoxy, or acombination thereof. In some embodiments, the modified nucleosidecomprises a LNA. In some embodiments, the modified nucleoside comprisesa 2′,4′ constrained ethyl nucleic acid. In some embodiments, themodified nucleoside comprises a 2′-O-methyl nucleoside, 2′-deoxyfluoronucleoside, 2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl(2′-O-AP) nucleoside, or 2′-ara-F, or a combination thereof. In someembodiments, the modified nucleoside comprises one or more 2′fluoromodified nucleosides. In some embodiments, the modified nucleosidecomprises a 2′ O-alkyl modified nucleoside. In some embodiments, theoligonucleotide comprises a lipid attached at a 3′ or 5′ terminus of theoligonucleotide. In some embodiments, the lipid comprises cholesterol,myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl,docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or acombination thereof. In some embodiments, the oligonucleotide comprisesan N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. Insome embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modifiednucleosides. In some embodiments, the oligonucleotide comprises 2 ormore modified nucleosides, 3 or more modified nucleosides, 4 or moremodified nucleosides, 5 or more modified nucleosides, 6 or more modifiednucleosides, 7 or more modified nucleosides, 8 or more modifiednucleosides, 9 or more modified nucleosides, 10 or more modifiednucleosides, 11 or more modified nucleosides, 12 or more modifiednucleosides, 13 or more modified nucleosides, 14 or more modifiednucleosides, 15 or more modified nucleosides, 16 or more modifiednucleosides, 17 or more modified nucleosides, 18 or more modifiednucleosides, 19 or more modified nucleosides, 20 or more modifiednucleosides, or 21 or more modified nucleosides. In some embodiments,the sense strand comprises modification pattern 1S. In some embodiments,the sense strand comprises modification pattern 2S. In some embodiments,the sense strand comprises modification pattern 3S. In some embodiments,the sense strand comprises modification pattern 4S. In some embodiments,the sense strand comprises modification pattern 5S. In some embodiments,the sense strand comprises modification pattern 6S. In some Any ofmodification patterns 1S-6S may include a GalNAc ligand at the 5′ or 3′end. In some embodiments, the antisense strand comprises modificationpattern 1AS. In some embodiments, the antisense strand comprisesmodification pattern 2AS. In some embodiments, the antisense strandcomprises modification pattern 3AS. In some embodiments, the antisensestrand comprises modification pattern 4AS. In some embodiments, theantisense strand comprises modification pattern 5AS. In someembodiments, the antisense strand comprises modification pattern 6AS. Insome embodiments, the antisense strand comprises modification pattern7AS. In some embodiments, the antisense strand comprises modificationpattern 8AS. In some embodiments, the antisense strand comprisesmodification pattern 9AS. Any of modification patterns 1AS-9AS mayinclude a GalNAc ligand at the 5′ or 3′ end. In some embodiments, thesense strand comprises modification pattern 15 and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand comprises modificationpattern 2S and the antisense strand comprises modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, thesense strand comprises modification pattern 3S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand comprises modificationpattern 4S and the antisense strand comprises modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, thesense strand comprises modification pattern 5S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand comprises modificationpattern 6S and the antisense strand comprises modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, thesense strand comprises a nucleoside sequence comprising or consistingthe sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions, and modification pattern 1S. In someembodiments, the sense strand comprises a nucleoside sequence comprisingor consisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 15. In some embodiments, the sensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleicacid sequence thereof having 1 or 2 nucleoside substitutions, additions,or deletions, and modification pattern 2S. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 1AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1855-3708 or 13978-13985, and modification pattern 1AS. In someembodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1855-3708 or 13978-13985, or a nucleic acid sequence thereof having 1 or2 nucleoside substitutions, additions, or deletions, and modificationpattern 3AS. In some embodiments, the antisense strand comprises anucleoside sequence comprising or consisting of the sequence of any oneof SEQ ID NOs: 1855-3708 or 13978-13985, and modification pattern 3AS.In some embodiments, the oligonucleotide comprises an ASO. In someembodiments, the ASO is 12-30 nucleosides in length. Also disclosedherein are compositions comprising an oligonucleotide that inhibits theexpression of ANGPTL4, wherein the oligonucleotide comprises anantisense oligonucleotide (ASO) about 12-30 nucleosides in length andcomprising a nucleoside sequence complementary to about 12-30 contiguousnucleosides of SEQ ID NO: 13935; wherein (i) the oligonucleotidecomprises a modification comprising a modified nucleoside and/or amodified internucleoside linkage, and/or (ii) the composition comprisesa pharmaceutically acceptable carrier. Also disclosed herein arecompositions comprising an oligonucleotide that inhibits the expressionof ANGPTL4, wherein the oligonucleotide comprises an ASO about 12-30nucleosides in length and comprising a nucleoside sequence complementaryto about 12-30 contiguous nucleosides of SEQ ID NO: 13936; wherein (i)the oligonucleotide comprises a modification comprising a modifiednucleoside and/or a modified internucleoside linkage, and/or (ii) thecomposition comprises a pharmaceutically acceptable carrier. In someembodiments, the ASO comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 3709-13934, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the ASO comprises anucleoside sequence comprising or consisting of the sequence of any oneof SEQ ID NOs: 3709-13934. In some embodiments, the ASO comprisesmodification pattern:5′-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3′ where “dN” isany deoxynucleotide, “n” is a 2′O-methyl or 2′O-methoxyethyl-modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the ASO comprises one or more of a locked nucleic acid (LNA) or a 2′,4′constrained ethyl nucleic acid. In some embodiments, the ASO comprises anucleoside sequence comprising or consisting of the sequence of any oneof SEQ ID NOs: 3709-13934, or a nucleic acid sequence thereof having 1or 2 nucleoside substitutions, additions, or deletions, and modificationpattern ASO1. In some embodiments, the ASO comprises a nucleosidesequence comprising or consisting of the sequence of any one of SEQ IDNOs: 3709-13934, and modification pattern ASO1. In some embodiments, thecomposition is a pharmaceutical composition. In some embodiments, thecomposition is sterile. Some embodiments comprise a pharmaceuticallyacceptable carrier. In some embodiments, the pharmaceutically acceptablecarrier comprises water, a buffer, or a saline solution.

Disclosed herein are methods of treating a cardiometabolic disorder in asubject in need thereof, the method comprising administering to thesubject a composition comprising an oligonucleotide that targetsANGPTL4. In some embodiments, the cardiometabolic disorder comprises acardiovascular disorder. In some embodiments, the cardiometabolicdisorder comprises a metabolic disorder. Also disclosed herein aremethods of treating a metabolic disorder in a subject in need thereof,the method comprising administering to the subject a compositioncomprising an oligonucleotide that targets ANGPTL4. In some embodiments,the metabolic disorder comprises hyperlipidemia. In some embodiments,the metabolic disorder comprises hypertriglyceridemia. In someembodiments, the metabolic disorder comprises diabetes. In someembodiments, the metabolic disorder comprises type 2 diabetes. Alsodisclosed herein are methods of treating a cardiovascular disorder in asubject in need thereof, the method comprising administering to thesubject a composition comprising an oligonucleotide that targetsANGPTL4. In some embodiments, the cardiovascular disorder comprisesheart disease. In some embodiments, the cardiovascular disordercomprises myocardial infarction. In some embodiments, the cardiovasculardisorder comprises angina pectoris. In some embodiments, thecardiovascular disorder comprises atherosclerosis. In some embodiments,the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, amouse, a rat, a primate, or a monkey. In some embodiments, the subjectis a human. In some embodiments, the subject is ≥40 years of age. Insome embodiments, the subject is ≤85 years of age. In some embodiments,the subject is ≥40 and ≤85 years of age. In some embodiments, a baselinemeasurement is obtained in a sample obtained from the subject prior toadministering the composition to the subject. In some embodiments, thebaseline measurement is a baseline triglyceride measurement. In someembodiments, the baseline measurement is a baseline cholesterolmeasurement. In some embodiments, the baseline measurement is a baselineHDL measurement. In some embodiments, the baseline measurement is abaseline glucose measurement. In some embodiments, the baselinemeasurement is a baseline insulin measurement. In some embodiments, thebaseline measurement is a baseline ANGPTL4 protein measurement. In someembodiments, the sample is a blood, plasma, or serum sample. In someembodiments, the sample is a serum sample. In some embodiments, thebaseline measurement is obtained by an immunoassay, a colorimetricassay, or a fluorescence assay. In some embodiments, the baselinemeasurement is a baseline ANGPTL4 mRNA measurement. In some embodiments,the sample is a tissue sample. In some embodiments, the tissue samplecomprises liver, adipose, small intestine, mesenteric lymph node, orcardiac tissue. In some embodiments, the tissue sample is a liversample. In some embodiments, the baseline measurement is obtained byPCR. In some embodiments, the sample is obtained from the subject afteran overnight fasting period. In some embodiments, the sample is obtainedfrom the subject in a fed state. In some embodiments, the compositionreduces circulating triglycerides relative to the baseline triglyceridemeasurement. In some embodiments, the reduced triglycerides are measuredin a second sample obtained from the subject after administering thecomposition to the subject. In some embodiments, the composition reducescirculating cholesterol relative to the baseline cholesterolmeasurement. In some embodiments, the reduced cholesterol is measured ina second sample obtained from the subject after administering thecomposition to the subject. In some embodiments, the compositionincreases circulating HDL relative to the baseline HDL measurement. Insome embodiments, the increased HDL is measured in a second sampleobtained from the subject after administering the composition to thesubject. In some embodiments, the composition reduces circulatingglucose relative to the baseline glucose measurement. In someembodiments, the reduced glucose is measured in a second sample obtainedfrom the subject after administering the composition to the subject. Insome embodiments, the composition reduces circulating ANGPTL4 proteinlevels relative to the baseline ANGPTL4 protein measurement. In someembodiments, the reduced ANGPTL4 protein levels are measured in a secondsample obtained from the subject after administering the composition tothe subject. In some embodiments, the composition reduces ANGPTL4 mRNAlevels relative to the baseline ANGPTL4 mRNA measurement. In someembodiments, the reduced ANGPTL4 mRNA levels are measured in a secondsample obtained from the subject after administering the composition tothe subject. In some embodiments, the oligonucleotide comprises an siRNAcomprising a sense strand and an antisense strand. In some embodiments,the sense strand is 14-30 nucleosides in length. In some embodiments,the antisense strand is 14-30 nucleosides in length. In someembodiments, the oligonucleotide comprises an siRNA comprising a sensestrand and an antisense strand, each strand is independently about 14-30nucleosides in length, and at least one of the sense strand and theantisense strand comprises a nucleoside sequence comprising about 14-30contiguous nucleosides of SEQ ID NO: 13935. In some embodiments, theoligonucleotide comprises an siRNA comprising a sense strand and anantisense strand, each strand is independently about 14-30 nucleosidesin length, and at least one of the sense strand and the antisense strandcomprises a nucleoside sequence comprising about 14-30 contiguousnucleosides of SEQ ID NO: 13936. In some embodiments, the sense strandand the antisense strand form a double-stranded RNA duplex. In someembodiments, the first base pair of the double-stranded RNA duplex is anAU base pair. In some embodiments, the sense strand comprises anucleoside sequence comprising or consisting of the sequence of any oneof SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises a nucleoside sequence comprisingor consisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977. In some embodiments, the sense strand further comprises a3′ overhang comprising 1, 2, or more nucleosides. In some embodiments,the antisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985. In some embodiments, the antisense strand further comprisesa 3′ overhang comprising 1, 2, or more nucleosides. In some embodiments,the siRNA binds with a 19mer in a human ANGPTL4 mRNA. In someembodiments, the siRNA binds with a 17mer in a non-human primate ANGPTL4mRNA. In some embodiments, the siRNA binds with a 19mer in a humanANGPTL4 mRNA. In some embodiments, the siRNA binds with a human ANGPTL4mRNA and less than or equal to 20 human off-targets, with no more than 2mismatches in the antisense strand. In some embodiments, siRNA bindswith a human ANGPTL4 mRNA target site that does not harbor an SNP, witha minor allele frequency (MAF) greater or equal to 1% (pos. 2-18). Insome embodiments, the sense strand comprises the nucleoside sequence ofany one of SEQ ID NOs: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63,64, 79, 80, 84, 111, 112, 116, 117, 118, 119, 120, 121, 125, 126, 127,128, 129, 149, 150, 152, 153, 154, 157, 158, 159, 161, 164, 165, 166,167, 168, 169, 172, 174, 175, 177, 196, 198, 199, 210, 211, 212, 214,215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245,246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272,274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326,328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349,350, 352, 353, 356, 377, 380, 382, 386, 388, 391, 392, 393, 394, 397,398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421,422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506,509, 517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612,616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676,677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834,841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868,871, 872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911,912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968,1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052,1053, 1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133,1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158,1161, 1162, 1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184,1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347,1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416,1417, 1418, 1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519,1523, 1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581,1589, 1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613,1614, 1617, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745,1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798,1799, 1800, 1801, 1802, or 1803, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions; and/orthe antisense strand comprises the nucleoside sequence of any one of SEQID NOs: 1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915,1916, 1917, 1918, 1933, 1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973,1974, 1975, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007, 2008,2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028,2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066, 2068, 2069, 2070, 2071,2072, 2073, 2075, 2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100,2104, 2106, 2107, 2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125,2126, 2128, 2134, 2136, 2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175,2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191,2192, 2193, 2196, 2201, 2203, 2204, 2206, 2207, 2210, 2231, 2234, 2236,2240, 2242, 2245, 2246, 2247, 2248, 2251, 2252, 2253, 2256, 2258, 2259,2265, 2266, 2267, 2268, 2269, 2271, 2273, 2274, 2275, 2276, 2277, 2278,2279, 2280, 2281, 2282, 2283, 2284, 2285, 2289, 2335, 2338, 2360, 2363,2371, 2373, 2374, 2419, 2424, 2425, 2426, 2443, 2461, 2462, 2464, 2465,2466, 2470, 2471, 2474, 2477, 2489, 2491, 2494, 2497, 2507, 2526, 2527,2528, 2529, 2530, 2531, 2532, 2533, 2535, 2536, 2537, 2538, 2540, 2541,2543, 2546, 2549, 2684, 2688, 2695, 2696, 2697, 2698, 2704, 2705, 2706,2707, 2708, 2710, 2711, 2713, 2720, 2722, 2725, 2726, 2730, 2741, 2742,2744, 2746, 2747, 2748, 2751, 2754, 2756, 2761, 2765, 2766, 2767, 2768,2769, 2770, 2771, 2772, 2773, 2774, 2775, 2776, 2779, 2799, 2822, 2855,2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882, 2886, 2891, 2906, 2907,2908, 2909, 2911, 2912, 2918, 2966, 2976, 2978, 2980, 2981, 2987, 2988,2990, 2991, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015,3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029, 3035, 3036, 3038, 3102,3103, 3106, 3107, 3113, 3130, 3139, 3164, 3169, 3192, 3197, 3201, 3202,3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267, 3268, 3269, 3270, 3271,3272, 3283, 3284, 3302, 3331, 3341, 3342, 3343, 3347, 3348, 3373, 3377,3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425, 3426, 3434, 3435, 3443,3451, 3452, 3455, 3456, 3457, 3458, 3459, 3460, 3464, 3465, 3467, 3468,3471, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601,3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653,3654, 3655, 3656, or 3657, or a nucleic acid sequence thereof having 1or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises the nucleoside sequence of anyone of SEQ ID NOs: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64,79, 80, 84, 111, 112, 116, 117, 118, 119, 120, 121, 125, 126, 127, 128,129, 149, 150, 152, 153, 154, 157, 158, 159, 161, 164, 165, 166, 167,168, 169, 172, 174, 175, 177, 196, 198, 199, 210, 211, 212, 214, 215,216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245, 246,250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274,280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328,329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350,352, 353, 356, 377, 380, 382, 386, 388, 391, 392, 393, 394, 397, 398,399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421, 422,423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506, 509,517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612, 616,617, 620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676, 677,678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834, 841,842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868, 871,872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911, 912,913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968, 1001,1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053,1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134,1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161,1162, 1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248,1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348,1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417,1418, 1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523,1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589,1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613, 1614,1617, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747,1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799,1800, 1801, 1802, or 1803; and/or the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1886, 1887, 1888, 1889,1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1938,1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982,1983, 2003, 2004, 2006, 2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019,2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064,2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075, 2076, 2077, 2082,2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107, 2108, 2109, 2114,2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134, 2136, 2143, 2144,2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184,2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2204,2206, 2207, 2210, 2231, 2234, 2236, 2240, 2242, 2245, 2246, 2247, 2248,2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267, 2268, 2269, 2271,2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284,2285, 2289, 2335, 2338, 2360, 2363, 2371, 2373, 2374, 2419, 2424, 2425,2426, 2443, 2461, 2462, 2464, 2465, 2466, 2470, 2471, 2474, 2477, 2489,2491, 2494, 2497, 2507, 2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533,2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546, 2549, 2684, 2688, 2695,2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710, 2711, 2713, 2720,2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746, 2747, 2748, 2751, 2754,2756, 2761, 2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774,2775, 2776, 2779, 2799, 2822, 2855, 2856, 2859, 2860, 2863, 2864, 2865,2867, 2882, 2886, 2891, 2906, 2907, 2908, 2909, 2911, 2912, 2918, 2966,2976, 2978, 2980, 2981, 2987, 2988, 2990, 2991, 3001, 3002, 3003, 3005,3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025,3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106, 3107, 3113, 3130, 3139,3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259,3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341,3342, 3343, 3347, 3348, 3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419,3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458,3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 3553, 3555, 3556, 3557,3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633,3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656, or 3657. In someembodiments, the sense strand comprises the nucleoside sequence of anyone of SEQ ID NOs: 33, 34, 35, 36, 56, 121, 272, 280, 282, 289, 290,291, 292, 293, 321, 323, 326, 328, 329, 330, 331, 332, 333, 334, 335,337, 338, 339, 342, 347, 349, 411, 412, 430, 431, 435, 481, 484, 509,517, 519, 520, 565, 620, 635, 637, 640, 830, 834, 841, 842, 843, 844,850, 871, 872, 876, 887, 888, 894, 897, 902, 945, 1001, 1002, 1005,1037, 1133, 1134, 1137, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161,1162, 1164, 1165, 1166, 1171, 1172, 1248, 1249, 1315, 1338, 1343, 1347,1348, 1429, 1430, 1570, 1571, 1572, 1610, 1611, 1617, 1780, 1784, or1787, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, theantisense strand comprises the nucleoside sequence of any one of SEQ IDNOs: 1887, 1888, 1889, 1890, 1910, 1975, 2126, 2134, 2136, 2143, 2144,2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187,2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285,2289, 2335, 2338, 2363, 2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494,2684, 2688, 2695, 2696, 2697, 2698, 2704, 2725, 2726, 2730, 2741, 2742,2748, 2751, 2756, 2799, 2855, 2856, 2859, 2891, 2987, 2988, 2991, 3003,3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020, 3025,3026, 3102, 3103, 3169, 3192, 3197, 3201, 3202, 3283, 3284, 3424, 3425,3426, 3464, 3465, 3471, 3634, 3638, or 3641, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions.In some embodiments, the sense strand comprises the nucleoside sequenceof any one of SEQ ID NOs: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62,63, 64, 79, 80, 112, 116, 117, 118, 119, 120, 125, 126, 127, 128, 129,149, 150, 152, 153, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169,172, 174, 175, 196, 199, 211, 212, 214, 215, 216, 217, 218, 219, 221,222, 223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255,260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 289, 290, 291, 292,293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334,335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 380, 382, 386,388, 391, 392, 393, 394, 397, 398, 399, 402, 404, 405, 411, 412, 413,414, 415, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431,435, 484, 517, 519, 520, 565, 570, 571, 572, 607, 608, 610, 611, 612,616, 617, 620, 635, 637, 640, 672, 673, 674, 675, 676, 677, 678, 679,681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 841, 842, 843, 844,850, 851, 852, 853, 854, 856, 857, 866, 868, 871, 872, 876, 887, 888,890, 892, 893, 894, 902, 911, 912, 913, 914, 915, 916, 917, 918, 919,920, 921, 922, 945, 1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013,1028, 1032, 1052, 1053, 1054, 1055, 1057, 1058, 1112, 1122, 1124, 1126,1127, 1133, 1134, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158,1161, 1162, 1164, 1165, 1166, 1175, 1182, 1184, 1252, 1253, 1259, 1276,1285, 1310, 1315, 1343, 1347, 1348, 1349, 1350, 1351, 1405, 1407, 1413,1414, 1415, 1416, 1417, 1418, 1429, 1430, 1448, 1519, 1523, 1556, 1561,1563, 1564, 1565, 1571, 1572, 1580, 1581, 1589, 1597, 1601, 1602, 1603,1604, 1605, 1606, 1611, 1613, 1614, 1693, 1699, 1701, 1702, 1703, 1722,1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780,1784, 1788, 1798, 1799, 1801, 1802, or 1803, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions.In some embodiments, the antisense strand comprises the nucleosidesequence of any one of SEQ ID NOs: 1886, 1887, 1888, 1889, 1890, 1910,1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1966, 1970, 1971,1972, 1973, 1974, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007,2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028,2029, 2050, 2053, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075,2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107,2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134,2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182,2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201,2203, 2204, 2206, 2207, 2210, 2234, 2236, 2240, 2242, 2245, 2246, 2247,2248, 2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267, 2268, 2269,2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285,2289, 2338, 2371, 2373, 2374, 2419, 2424, 2425, 2426, 2461, 2462, 2464,2465, 2466, 2470, 2471, 2474, 2489, 2491, 2494, 2526, 2527, 2528, 2529,2530, 2531, 2532, 2533, 2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546,2549, 2684, 2695, 2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710,2711, 2720, 2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746, 2747, 2748,2756, 2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774, 2775,2776, 2799, 2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882, 2886,2906, 2907, 2908, 2909, 2911, 2912, 2966, 2976, 2978, 2980, 2981, 2987,2988, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016,3018, 3019, 3020, 3029, 3036, 3038, 3106, 3107, 3113, 3130, 3139, 3164,3169, 3197, 3201, 3202, 3203, 3204, 3205, 3259, 3261, 3267, 3268, 3269,3270, 3271, 3272, 3283, 3284, 3302, 3373, 3377, 3410, 3415, 3417, 3418,3419, 3425, 3426, 3434, 3435, 3443, 3451, 3455, 3456, 3457, 3458, 3459,3460, 3465, 3467, 3468, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595,3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3642,3652, 3653, 3655, 3656, or 3657, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises the nucleoside sequence of anyone of SEQ ID NOs: 33, 34, 35, 36, 56, 272, 280, 289, 290, 291, 292,293, 321, 323, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338,339, 342, 347, 349, 411, 412, 430, 431, 435, 484, 517, 519, 520, 565,620, 635, 637, 640, 830, 841, 842, 843, 844, 850, 871, 872, 876, 887,888, 894, 902, 945, 1001, 1002, 1005, 1133, 1134, 1149, 1151, 1153,1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1315, 1343, 1347,1348, 1429, 1430, 1571, 1572, 1611, 1780, or 1784, or a nucleic acidsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions. In some embodiments, the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1887, 1888, 1889, 1890,1910, 2126, 2134, 2143, 2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182,2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201,2203, 2265, 2266, 2284, 2285, 2289, 2338, 2371, 2373, 2374, 2419, 2474,2489, 2491, 2494, 2684, 2695, 2696, 2697, 2698, 2704, 2725, 2726, 2730,2741, 2742, 2748, 2756, 2799, 2855, 2856, 2859, 2987, 2988, 3003, 3005,3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020, 3169, 3197,3201, 3202, 3283, 3284, 3425, 3426, 3465, 3634, or 3638. In someembodiments, the antisense strand comprises a seed region that is notidentical to a seed region of a human miRNA. In some embodiments, thesense strand comprises the nucleoside sequence of any one of SEQ ID NOs:32, 36, 56, 57, 58, 61, 62, 79, 80, 117, 119, 125, 126, 128, 149, 152,157, 158, 159, 161, 165, 166, 167, 168, 169, 174, 196, 211, 212, 217,218, 219, 230, 231, 245, 246, 253, 260, 261, 262, 271, 272, 280, 289,291, 292, 293, 304, 321, 323, 325, 326, 328, 330, 331, 332, 333, 334,337, 338, 342, 347, 349, 352, 353, 356, 380, 382, 386, 388, 391, 392,394, 399, 413, 414, 415, 422, 423, 424, 425, 426, 435, 517, 519, 520,565, 571, 607, 608, 612, 617, 620, 635, 640, 672, 673, 674, 675, 678,679, 681, 683, 684, 687, 692, 842, 843, 850, 851, 854, 866, 868, 876,892, 893, 902, 911, 912, 913, 914, 916, 919, 945, 1001, 1002, 1006,1010, 1028, 1052, 1053, 1054, 1055, 1057, 1112, 1124, 1127, 1147, 1149,1151, 1153, 1155, 1157, 1164, 1175, 1182, 1184, 1259, 1276, 1285, 1315,1343, 1349, 1350, 1351, 1405, 1407, 1413, 1415, 1418, 1564, 1571, 1581,1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1613, 1614, 1693, 1701,1722, 1740, 1745, 1751, 1755, 1801, 1802, or 1803, or 3638, or a nucleicacid sequence thereof having 1 or 2 nucleoside substitutions, additions,or deletions. In some embodiments, the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1886, 1890, 1910, 1911,1912, 1915, 1916, 1933, 1934, 1971, 1973, 1979, 1980, 1982, 2003, 2006,2011, 2012, 2013, 2015, 2019, 2020, 2021, 2022, 2023, 2028, 2050, 2065,2066, 2071, 2072, 2073, 2084, 2085, 2099, 2100, 2107, 2114, 2115, 2116,2125, 2126, 2134, 2143, 2145, 2146, 2147, 2158, 2175, 2177, 2179, 2180,2182, 2184, 2185, 2186, 2187, 2188, 2191, 2192, 2196, 2201, 2203, 2206,2207, 2210, 2234, 2236, 2240, 2242, 2245, 2246, 2248, 2253, 2267, 2268,2269, 2276, 2277, 2278, 2279, 2280, 2289, 2371, 2373, 2374, 2419, 2425,2461, 2462, 2466, 2471, 2474, 2489, 2494, 2526, 2527, 2528, 2529, 2532,2533, 2535, 2537, 2538, 2541, 2546, 2696, 2697, 2704, 2705, 2708, 2720,2722, 2730, 2746, 2747, 2756, 2765, 2766, 2767, 2768, 2770, 2773, 2799,2855, 2856, 2860, 2864, 2882, 2906, 2907, 2908, 2909, 2911, 2966, 2978,2981, 3001, 3003, 3005, 3007, 3009, 3011, 3018, 3029, 3036, 3038, 3113,3130, 3139, 3169, 3197, 3203, 3204, 3205, 3259, 3261, 3267, 3269, 3272,3418, 3425, 3435, 3443, 3451, 3455, 3456, 3457, 3458, 3459, 3460, 3467,3468, 3547, 3555, 3576, 3594, 3599, 3605, 3609, 3655, 3656, or 3657, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the sense strand comprisesthe nucleoside sequence of any one of SEQ ID 36, 56, 272, 280, 289, 291,292, 293, 321, 323, 326, 328, 330, 331, 332, 333, 334, 337, 338, 342,347, 349, 435, 517, 519, 520, 565, 620, 635, 640, 842, 843, 850, 876,902, 945, 1001, 1002, 1149, 1151, 1153, 1155, 1157, 1164, 1315, 1343, or1571, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, theantisense strand comprises the nucleoside sequence of any one of SEQ ID1890, 1910, 2126, 2134, 2143, 2145, 2146, 2147, 2175, 2177, 2180, 2182,2184, 2185, 2186, 2187, 2188, 2191, 2192, 2196, 2201, 2203, 2289, 2371,2373, 2374, 2419, 2474, 2489, 2494, 2696, 2697, 2704, 2730, 2756, 2799,2855, 2856, 3003, 3005, 3007, 3009, 3011, 3018, 3169, 3197, or 3425, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the sense strand comprisesa seed region that is not identical to a seed region of a human miRNA.In some embodiments, the sense strand comprises the nucleoside sequenceof any one of SEQ ID NOs: 32, 36, 56, 58, 61, 62, 80, 117, 119, 126,152, 154, 157, 158, 159, 161, 166, 169, 174, 177, 196, 211, 212, 217,218, 230, 231, 245, 253, 260, 261, 271, 272, 280, 289, 293, 304, 328,330, 331, 332, 333, 334, 337, 342, 347, 349, 353, 356, 386, 388, 391,392, 394, 414, 415, 422, 423, 424, 426, 435, 520, 571, 608, 612, 617,653, 672, 678, 679, 681, 683, 692, 842, 843, 851, 854, 859, 876, 892,900, 913, 914, 919, 968, 1001, 1002, 1054, 1057, 1064, 1112, 1124, 1157,1164, 1182, 1184, 1248, 1259, 1343, 1351, 1352, 1415, 1418, 1564, 1581,1602, 1614, 1693, 1701, 1722, 1740, 1751, 1755, or 1787, or a nucleicacid sequence thereof having 1 or 2 nucleoside substitutions, additions,or deletions. In some embodiments, the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1886, 1890, 1910, 1912,1915, 1916, 1934, 1971, 1973, 1980, 2006, 2008, 2011, 2012, 2013, 2015,2020, 2023, 2028, 2031, 2050, 2065, 2066, 2071, 2072, 2084, 2085, 2099,2107, 2114, 2115, 2125, 2126, 2134, 2143, 2147, 2158, 2182, 2184, 2185,2186, 2187, 2188, 2191, 2196, 2201, 2203, 2207, 2210, 2240, 2242, 2245,2246, 2248, 2268, 2269, 2276, 2277, 2278, 2280, 2289, 2374, 2425, 2462,2466, 2471, 2507, 2526, 2532, 2533, 2535, 2537, 2546, 2696, 2697, 2705,2708, 2713, 2730, 2746, 2754, 2767, 2768, 2773, 2822, 2855, 2856, 2908,2911, 2918, 2966, 2978, 3011, 3018, 3036, 3038, 3102, 3113, 3197, 3205,3206, 3269, 3272, 3418, 3435, 3456, 3468, 3547, 3555, 3576, 3594, 3605,3609, or 3641, or a nucleic acid sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the sense strand comprises the nucleoside sequence of any one of SEQ IDNOs: 36, 56, 272, 280, 289, 293, 328, 330, 331, 332, 333, 334, 337, 342,347, 349, 435, 520, 842, 843, 876, 1001, 1002, 1157, 1164, or 1343, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the antisense strandcomprises the nucleoside sequence of any one of SEQ

ID NOs: 1890, 1910, 2126, 2134, 2143, 2147, 2182, 2184, 2185, 2186,2187, 2188, 2191, 2196, 2201, 2203, 2289, 2374, 2696, 2697, 2730, 2855,2856, 3011, 3018, or 3197, or a nucleic acid sequence thereof having 1or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand and/or the antisense strand furthercomprise a 3′ overhang comprising 1, 2, or more nucleosides. In someembodiments, the 3′ overhang comprises 2 nucleosides. In someembodiments, (i) the oligonucleotide comprises a modification comprisinga modified nucleoside and/or a modified internucleoside linkage, and/or(ii) the composition comprises a pharmaceutically acceptable carrier. Insome embodiments, the oligonucleotide comprises a modificationcomprising a modified nucleoside and/or a modified internucleosidelinkage. In some embodiments, the oligonucleotide comprises a modifiedinternucleoside linkage. In some embodiments, the modifiedinternucleoside linkage comprises alkylphosphonate, phosphorothioate,methylphosphonate, phosphorodithioate, alkylphosphonothioate,phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate,or carboxymethyl ester, or a combination thereof. In some embodiments,the modified internucleoside linkage comprises one or morephosphorothioate linkages. In some embodiments, the oligonucleotidecomprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 20 modified internucleoside linkages. In some embodiments, theoligonucleotide comprises 2 or more modified internucleoside linkages, 3or more modified internucleoside linkages, 4 or more modifiedinternucleoside linkages, 5 or more modified internucleoside linkages, 6or more modified internucleoside linkages, 7 or more modifiedinternucleoside linkages, 8 or more modified internucleoside linkages, 9or more modified internucleoside linkages, 10 or more modifiedinternucleoside linkages, 11 or more modified internucleoside linkages,12 or more modified internucleoside linkages, 13 or more modifiedinternucleoside linkages, 14 or more modified internucleoside linkages,15 or more modified internucleoside linkages, 16 or more modifiedinternucleoside linkages, 17 or more modified internucleoside linkages,18 or more modified internucleoside linkages, 19 or more modifiedinternucleoside linkages, or 20 or more modified internucleosidelinkages. In some embodiments, the oligonucleotide comprises themodified nucleoside. In some embodiments, the modified nucleosidecomprises a locked nucleic acid (LNA), hexitol nucleic acid (HLA),cyclohexene nucleic acid (CeNA), 2′-methoxyethyl, 2′-O-alkyl,2′-O-allyl, 2′-O-allyl, 2′-fluoro, or 2′-deoxy, or a combinationthereof. In some embodiments, the modified nucleoside comprises a LNA.In some embodiments, the modified nucleoside comprises a 2′,4′constrained ethyl nucleic acid. In some embodiments, the modifiednucleoside comprises a 2′-O-methyl nucleoside, 2′-deoxyfluoronucleoside, 2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl(2′-O-AP) nucleoside, or 2′-ara-F, or a combination thereof. In someembodiments, the modified nucleoside comprises one or more 2′fluoromodified nucleosides. In some embodiments, the modified nucleosidecomprises a 2′ O-alkyl modified nucleoside. In some embodiments, theoligonucleotide comprises a lipid attached at a 3′ or 5′ terminus of theoligonucleotide. In some embodiments, the lipid comprises cholesterol,myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl,docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or acombination thereof. In some embodiments, the oligonucleotide comprisesan N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. Insome embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modifiednucleosides. In some embodiments, the oligonucleotide comprises 2 ormore modified nucleosides, 3 or more modified nucleosides, 4 or moremodified nucleosides, 5 or more modified nucleosides, 6 or more modifiednucleosides, 7 or more modified nucleosides, 8 or more modifiednucleosides, 9 or more modified nucleosides, 10 or more modifiednucleosides, 11 or more modified nucleosides, 12 or more modifiednucleosides, 13 or more modified nucleosides, 14 or more modifiednucleosides, 15 or more modified nucleosides, 16 or more modifiednucleosides, 17 or more modified nucleosides, 18 or more modifiednucleosides, 19 or more modified nucleosides, 20 or more modifiednucleosides, or 21 or more modified nucleosides. In some embodiments,the sense strand comprises modification pattern 1S. In some embodiments,the sense strand comprises modification pattern 2S. In some embodiments,the sense strand comprises modification pattern 3S. In some embodiments,the sense strand comprises modification pattern 4S. In some embodiments,the sense strand comprises modification pattern 5S. In some embodiments,the sense strand comprises modification pattern 6S. In some Any ofmodification patterns 1S-6S may include a GalNAc ligand at the 5′ or 3′end. In some embodiments, the antisense strand comprises modificationpattern 1AS. In some embodiments, the antisense strand comprisesmodification pattern 2AS. In some embodiments, the antisense strandcomprises modification pattern 3AS. In some embodiments, the antisensestrand comprises modification pattern 4AS. In some embodiments, theantisense strand comprises modification pattern 5AS. In someembodiments, the antisense strand comprises modification pattern 6AS. Insome embodiments, the antisense strand comprises modification pattern7AS. In some embodiments, the antisense strand comprises modificationpattern 8AS. In some embodiments, the antisense strand comprisesmodification pattern 9AS. Any of modification patterns 1AS-9AS mayinclude a GalNAc ligand at the 5′ or 3′ end. In some embodiments, thesense strand comprises modification pattern 15 and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand comprises modificationpattern 2S and the antisense strand comprises modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, thesense strand comprises modification pattern 3S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand comprises modificationpattern 4S and the antisense strand comprises modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, thesense strand comprises modification pattern 5S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand comprises modificationpattern 6S and the antisense strand comprises modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, thesense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions, and modification pattern 1S. In someembodiments, the sense strand comprises a nucleoside sequence comprisingor consisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 15. In some embodiments, the sensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleicacid sequence thereof having 1 or 2 nucleoside substitutions, additions,or deletions, and modification pattern 2S. In some embodiments, thesense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, andmodification pattern 2S. In some embodiments, the antisense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1855-3708 or 13978-13985, or a nucleic acidsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions, and modification pattern 1AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, and modification pattern 1AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 3AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1855-3708 or 13978-13985, and modification pattern 3AS. In someembodiments, the oligonucleotide comprises an ASO. In some embodiments,the ASO is 12-30 nucleosides in length. In some embodiments, theoligonucleotide comprises an antisense oligonucleotide (ASO) about 12-30nucleosides in length and comprising a nucleoside sequence complementaryto about 12-30 contiguous nucleosides of SEQ ID NO: 13935; wherein (i)the oligonucleotide comprises a modification comprising a modifiednucleoside and/or a modified internucleoside linkage, and/or (ii) thecomposition comprises a pharmaceutically acceptable carrier. In someembodiments, the oligonucleotide comprises an ASO about 12-30nucleosides in length and comprising a nucleoside sequence complementaryto about 12-30 contiguous nucleosides of SEQ ID NO: 13936; wherein (i)the oligonucleotide comprises a modification comprising a modifiednucleoside and/or a modified internucleoside linkage, and/or (ii) thecomposition comprises a pharmaceutically acceptable carrier. In someembodiments, the ASO comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 3709-13934, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the ASO comprises anucleoside sequence comprising or consisting of the sequence of any oneof SEQ ID NOs: 3709-13934. In some embodiments, the ASO comprisesmodification pattern:5′-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3′ where “dN” isany deoxynucleotide, “n” is a 2′O-methyl or 2′O-methoxyethyl-modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the ASO comprises one or more of a locked nucleic acid (LNA) or a 2′,4′constrained ethyl nucleic acid. In some embodiments, the ASO comprises anucleoside sequence comprising or consisting of the sequence of any oneof SEQ ID NOs: 3709-13934, or a nucleic acid sequence thereof having 1or 2 nucleoside substitutions, additions, or deletions, and modificationpattern ASO1. In some embodiments, the ASO comprises a nucleosidesequence comprising or consisting of the sequence of any one of SEQ IDNOs: 3709-13934, and modification pattern ASO1. In some embodiments, thecomposition is a pharmaceutical composition. In some embodiments, thecomposition is sterile. In some embodiments, the composition comprises apharmaceutically acceptable carrier. In some embodiments, thepharmaceutically acceptable carrier comprises water, a buffer, or asaline solution.

DETAILED DESCRIPTION

Large-scale human genetic data can improve the success rate ofpharmaceutical discovery and development. A Genome Wide AssociationStudy (GWAS) may detect associations between genetic variants and traitsin a population sample. A GWAS may enable better understanding of thebiology of disease, and provide applicable treatments. A GWAS canutilize genotyping and/or sequencing data, and often involves anevaluation of millions of genetic variants that are relatively evenlydistributed across the genome. The most common GWAS design is thecase-control study, which involves comparing variant frequencies incases versus controls. If a variant has a significantly differentfrequency in cases versus controls, that variant is said to beassociated with disease. Association statistics that may be used in aGWAS are p-values, as a measure of statistical significance; odds ratios(OR), as a measure of effect size; or beta coefficients (beta), as ameasure of effect size. Researchers often assume an additive geneticmodel and calculate an allelic odds ratio, which is the increased (ordecreased) risk of disease conferred by each additional copy of anallele (compared to carrying no copies of that allele). An additionalconcept in design and interpretation of GWAS is that of linkagedisequilibrium, which is the non-random association of alleles. Thepresence of linkage disequilibrium can obfuscate which variant is“causal.”

Functional annotation of variants and/or wet lab experimentation canidentify the causal genetic variant identified via GWAS, and in manycases may lead to the identification of disease-causing genes. Inparticular, understanding the functional effect of a causal geneticvariant (for example, loss of protein function, gain of proteinfunction, increase in gene expression, or decrease in gene expression)may allow that variant to be used as a proxy for therapeutic modulationof the target gene, or to gain insight into potential therapeuticefficacy and safety of a therapeutic that modulates that target.

Identification of such gene-disease associations has provided insightsinto disease biology and may be used to identify novel therapeutictargets for the pharmaceutical industry. In order to translate thetherapeutic insights derived from human genetics, disease biology inpatients may be exogenously ‘programmed’ into replicating theobservation from human genetics. There are several potential options fortherapeutic modalities that may be brought to bear in translatingtherapeutic targets identified via human genetics into novel medicines.These may include well established therapeutic modalities such as smallmolecules and monoclonal antibodies, maturing modalities such asoligonucleotides, and emerging modalities such as gene therapy and geneediting. The choice of therapeutic modality can depend on severalfactors including the location of a target (for example, intracellular,extracellular, or secreted), a relevant tissue (for example, liver) anda relevant indication.

Cardiovascular and metabolic diseases are leading causes of death,accounting for about one-third of all deaths globally. Angiopoietin-likeproteins (ANGPTLs) are regulators of lipoprotein metabolism and mayserve as therapeutic targets for modulation of lipid levels andcardiometabolic disease risk. ANGPTLs are a family of eight proteinswith some functional similarities to angiopoietins. They typically havea characteristic structure that includes an N-terminal coiled-coildomain that mediates homo-oligomerization and a C-terminal fibrinogendomain involved in signaling.

Angiopoietin-like 4 (ANGPTL4; UniProt ID Q9BY76) is an endogenousinhibitor of lipoprotein lipase (LPL), an enzyme that hydrolyzestriglycerides contained in triglyceride-rich lipoproteins (TRLs) such aschylomicrons and very low-density lipoproteins. ANGPTL4 is a secretedprotein that in humans is often most highly expressed in the liver andadipose tissue. After cellular secretion, ANGPTL4 is often cleaved to 37kD C-terminal and 15 kD N-terminal fragment, and these oligomerizedN-terminal fragments inhibit LPL. In some embodiments, ANGPTL4 isglycosylated. In some embodiments, ANGPTL4 has a coiled-coil N-terminaldomain. In some embodiments, ANGPTL4 has a fibrinogen-like C-terminaldomain.

Circulating triglycerides are strong and independent positive predictorsof cardiovascular disease risk and all-cause mortality, and are alsopositively correlated with plasma glucose levels, risk of diabetes,metabolic syndrome, and pancreatitis. Additionally, mutations in TRLgenes may cause hereditary disorders including familial chylomicronemiasyndrome and familial hypertriglyceridemia. Here, it is shown thatgenetic variants that cause inactivation of ANGPTL4 in humans areassociated with decreased triglycerides, increased HDL and decreasedrisk of diabetes and cardiovascular disease. Therefore, inhibition ofANGPTL4 may serve as a therapeutic strategy for treatment of a range ofcardiometabolic diseases.

Disclosed herein are compositions comprising an oligonucleotide thattargets Angiopoietin-like 4 (ANGPTL4). The oligonucleotide may include asmall interfering RNA (siRNA) or an antisense oligonucleotide (ASO).Also provided herein are methods of treating a metabolic orcardiovascular disorder by providing an oligonucleotide that targetsANGPTL4 to a subject in need thereof.

I. Compositions

Disclosed herein, in some embodiments, are compositions comprising anoligonucleotide. In some embodiments, the composition comprises anoligonucleotide that targets Angiopoietin-like 4 (ANGPTL4). In someembodiments, the composition consists of an oligonucleotide that targetsANGPTL4. In some embodiments, a composition described herein is used ina method of treating a disorder in a subject in need thereof. Someembodiments relate to a composition comprising an oligonucleotide foruse in a method of treating a disorder as described herein. Someembodiments relate to use of a composition comprising anoligonucleotide, in a method of treating a disorder as described herein.

In some embodiments, the composition comprises an oligonucleotide thattargets ANGPTL4 and when administered to a subject in an effectiveamount decreases ANGPTL4 mRNA levels in a cell or tissue. In someembodiments, the cell is a hepatocyte. In some embodiments, the tissueis liver or adipose tissue. In some embodiments, the ANGPTL4 mRNA levelsare decreased by about 2.5% or more, about 5% or more, or about 7.5% ormore, as compared to prior to administration. In some embodiments, theANGPTL4 mRNA levels are decreased by about 10% or more, as compared toprior to administration. In some embodiments, the ANGPTL4 mRNA levelsare decreased by about 20% or more, about 30% or more, about 40% ormore, about 50% or more, about 60% or more, about 70% or more, about 80%or more, about 90% or more, or about 100%, as compared to prior toadministration. In some embodiments, the ANGPTL4 mRNA levels aredecreased by no more than about 2.5%, no more than about 5%, or no morethan about 7.5%, as compared to prior to administration. In someembodiments, the ANGPTL4 mRNA levels are decreased by no more than about10%, as compared to prior to administration. In some embodiments, theANGPTL4 mRNA levels are decreased by no more than about 20%, no morethan about 30%, no more than about 40%, no more than about 50%, no morethan about 60%, no more than about 70%, no more than about 80%, or nomore than about 90%, as compared to prior to administration. In someembodiments, the ANGPTL4 mRNA levels are decreased by 2.5%, 5%, 7.5%,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a rangedefined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide thattargets ANGPTL4 and when administered to a subject in an effectiveamount decreases circulating ANGPTL4 protein levels in a cell or tissue.In some embodiments, the composition comprises an oligonucleotide thattargets ANGPTL4 and when administered to a subject in an effectiveamount decreases ANGPTL4 protein levels in a fluid such as blood, serumor plasma. In some embodiments, the ANGPTL4 protein levels are decreasedby about 2.5% or more, about 5% or more, or about 7.5% or more, ascompared to prior to administration. In some embodiments, the ANGPTL4protein levels are decreased by about 10% or more, as compared to priorto administration. In some embodiments, the ANGPTL4 protein levels aredecreased by about 20% or more, about 30% or more, about 40% or more,about 50% or more, about 60% or more, about 70% or more, about 80% ormore, about 90% or more, or about 100%, as compared to prior toadministration. In some embodiments, the ANGPTL4 protein levels aredecreased by no more than about 2.5%, no more than about 5%, or no morethan about 7.5%, as compared to prior to administration. In someembodiments, the ANGPTL4 protein levels are decreased by no more thanabout 10%, as compared to prior to administration. In some embodiments,the ANGPTL4 protein levels are decreased by no more than about 20%, nomore than about 30%, no more than about 40%, no more than about 50%, nomore than about 60%, no more than about 70%, no more than about 80%, orno more than about 90%, as compared to prior to administration. In someembodiments, the ANGPTL4 protein levels are decreased by 2.5%, 5%, 7.5%,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a rangedefined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide thattargets ANGPTL4 and when administered to a subject in an effectiveamount decreases circulating triglycerides. In some embodiments, thetriglycerides are decreased by about 2.5% or more, about 5% or more, orabout 7.5% or more, as compared to prior to administration. In someembodiments, the triglycerides are decreased by about 10% or more, ascompared to prior to administration. In some embodiments, thetriglycerides are decreased by about 20% or more, about 30% or more,about 40% or more, about 50% or more, about 60% or more, about 70% ormore, about 80% or more, about 90% or more, or about 100%, as comparedto prior to administration. In some embodiments, the triglycerides aredecreased by no more than about 2.5%, no more than about 5%, or no morethan about 7.5%, as compared to prior to administration. In someembodiments, the triglycerides are decreased by no more than about 10%,as compared to prior to administration. In some embodiments, thetriglycerides are decreased by no more than about 20%, no more thanabout 30%, no more than about 40%, no more than about 50%, no more thanabout 60%, no more than about 70%, no more than about 80%, or no morethan about 90%, as compared to prior to administration. In someembodiments, the triglycerides are decreased by 2.5%, 5%, 7.5%, 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range definedby any of the two aforementioned percentages.

In some embodiments the composition comprises an oligonucleotide thattargets ANGPTL4 and when administered to a subject in an effectiveamount decreases circulating cholesterol. In some embodiments, thecirculating cholesterol comprises circulating total cholesterol. In someembodiments, the circulating cholesterol is decreased by about 2.5% ormore, about 5% or more, or about 7.5% or more, as compared to prior toadministration. In some embodiments, the circulating cholesterol isdecreased by about 10% or more, as compared to prior to administration.In some embodiments, the circulating cholesterol is decreased by about20% or more, about 30% or more, about 40% or more, about 50% or more,about 60% or more, about 70% or more, about 80% or more, about 90% ormore, or about 100%, as compared to prior to administration. In someembodiments, the cholesterol is decreased by no more than about 2.5%, nomore than about 5%, or no more than about 7.5%, as compared to prior toadministration. In some embodiments, the cholesterol is decreased by nomore than about 10%, as compared to prior to administration. In someembodiments, the cholesterol is decreased by no more than about 20%, nomore than about 30%, no more than about 40%, no more than about 50%, nomore than about 60%, no more than about 70%, no more than about 80%, orno more than about 90%, as compared to prior to administration. In someembodiments, the circulating cholesterol is decreased by 2.5%, 5%, 7.5%,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a rangedefined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide thattargets ANGPTL4 and when administered to a subject in an effectiveamount increases circulating high-density lipoproteins (HDL). In someembodiments, the circulating HDL are increased by about 2.5% or more,about 5% or more, or about 7.5% or more, as compared to prior toadministration. In some embodiments, the circulating HDL are increasedby about 10% or more, as compared to prior to administration. In someembodiments, the circulating HDL are increased by about 20% or more,about 30% or more, about 40% or more, about 50% or more, about 60% ormore, about 70% or more, about 80% or more, about 90% or more, or about100% or more as compared to prior to administration. In someembodiments, the circulating HDL are increased by about 200% or more,about 300% or more, about 400% or more, about 500% or more, about 600%or more, about 700% or more, about 800% or more, about 900% or more, orabout 1000% or more, as compared to prior to administration. In someembodiments, the HDL is decreased by no more than about 2.5%, no morethan about 5%, or no more than about 7.5%, as compared to prior toadministration. In some embodiments, the HDL is decreased by no morethan about 10%, as compared to prior to administration. In someembodiments, the HDL is decreased by no more than about 20%, no morethan about 30%, no more than about 40%, no more than about 50%, no morethan about 60%, no more than about 70%, no more than about 80%, no morethan about 90%, or no more than about 100% as compared to prior toadministration. In some embodiments, the HDL is decreased by no morethan about 200%, no more than about 300%, no more than about 400%, nomore than about 500%, no more than about 600%, no more than about 700%,no more than about 800%, no more than about 900%, or no more than about1000%, as compared to prior to administration. In some embodiments, thecirculating HDL are increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 100%, 200% 300%, 400%, 500%, 600%, 700%, 800%,900%, 1000%, or by a range defined by any of the two aforementionedpercentages.

In some embodiments, the composition comprises an oligonucleotide thattargets ANGPTL4 and when administered to a subject in an effectiveamount decreases circulating glucose. In some embodiments, thecirculating glucose is decreased by about 2.5% or more, about 5% ormore, or about 7.5% or more, as compared to prior to administration. Insome embodiments, the circulating glucose is decreased by about 10% ormore, as compared to prior to administration. In some embodiments, thecirculating glucose is decreased by about 20% or more, about 30% ormore, about 40% or more, about 50% or more, about 60% or more, about 70%or more, about 80% or more, about 90% or more, or about 100%, ascompared to prior to administration. In some embodiments, the glucose isdecreased by no more than about 2.5%, no more than about 5%, or no morethan about 7.5%, as compared to prior to administration. In someembodiments, the glucose is decreased by no more than about 10%, ascompared to prior to administration. In some embodiments, the glucose isdecreased by no more than about 20%, no more than about 30%, no morethan about 40%, no more than about 50%, no more than about 60%, no morethan about 70%, no more than about 80%, or no more than about 90%, ascompared to prior to administration. In some embodiments, thecirculating glucose is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of thetwo aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide thattargets ANGPTL4 and when administered to a subject in an effectiveamount increases insulin sensitivity. In some embodiments, the insulinsensitivity is increased by about 2.5% or more, about 5% or more, orabout 7.5% or more, as compared to prior to administration. In someembodiments, the insulin sensitivity is increased by about 10% or more,as compared to prior to administration. In some embodiments, the insulinsensitivity is increased by about 20% or more, about 30% or more, about40% or more, about 50% or more, about 60% or more, about 70% or more,about 80% or more, about 90% or more, or about 100%, or more as comparedto prior to administration. In some embodiments, the insulin sensitivityis increased by about 200% or more, about 300% or more, about 400% ormore, about 500% or more, about 600% or more, about 700% or more, about800% or more, about 900% or more, or about 1000% or more, as compared toprior to administration. In some embodiments, the insulin sensitivity isincreased by no more than about 2.5%, no more than about 5%, or no morethan about 7.5%, as compared to prior to administration. In someembodiments, the insulin sensitivity is increased by no more than about10%, as compared to prior to administration. In some embodiments, theinsulin sensitivity is increased by no more than about 20%, no more thanabout 30%, no more than about 40%, no more than about 50%, no more thanabout 60%, no more than about 70%, no more than about 80%, no more thanabout 90%, or no more than about 100% as compared to prior toadministration. In some embodiments, the insulin sensitivity isincreased by no more than about 200%, no more than about 300%, no morethan about 400%, no more than about 500%, no more than about 600%, nomore than about 700%, no more than about 800%, no more than about 900%,or no more than about 1000%, as compared to prior to administration. Insome embodiments, the insulin sensitivity is increased by 2.5%, 5%,7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% 300%,400%, 500%, 600%, 700%, 800%, 900%, 1000%, or by a range defined by anyof the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide thattargets ANGPTL4 and when administered to a subject in an effectiveamount decreases circulating insulin. In some embodiments, thecirculating insulin is decreased by about 2.5% or more, about 5% ormore, or about 7.5% or more, as compared to prior to administration. Insome embodiments, the circulating insulin is decreased by about 10% ormore, as compared to prior to administration. In some embodiments, thecirculating insulin is decreased by about 20% or more, about 30% ormore, about 40% or more, about 50% or more, about 60% or more, about 70%or more, about 80% or more, about 90% or more, or about 100%, ascompared to prior to administration. In some embodiments, the insulin isdecreased by no more than about 2.5%, no more than about 5%, or no morethan about 7.5%, as compared to prior to administration. In someembodiments, the insulin is decreased by no more than about 10%, ascompared to prior to administration. In some embodiments, the insulin isdecreased by no more than about 20%, no more than about 30%, no morethan about 40%, no more than about 50%, no more than about 60%, no morethan about 70%, no more than about 80%, or no more than about 90%, ascompared to prior to administration. In some embodiments, thecirculating insulin is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of thetwo aforementioned percentages.

A. siRNAs

In some embodiments, the composition comprises an oligonucleotide thattargets Angiopoietin-like 4 (ANGPTL4), wherein the oligonucleotidecomprises a small interfering RNA (siRNA). In some embodiments, thecomposition comprises an oligonucleotide that targets Angiopoietin-like4 (ANGPTL4), wherein the oligonucleotide comprises a small interferingRNA (siRNA) comprising a sense strand and an antisense strand. In someembodiments, the sense strand comprises RNA. In some embodiments, theantisense strand comprises RNA.

In some embodiments, the siRNA comprises a sense strand and an antisensestrand, the antisense strand being complementary with no more than 2mismatches to a portion of a nucleic acid having the nucleoside sequenceof SEQ ID NO: 13936, and each strand having 12 to 30 nucleotides. Insome embodiments, the siRNA comprises a sense strand and an antisensestrand, the antisense strand being complementary with no more than 2mismatches to a portion of a nucleic acid having the nucleoside sequenceof SEQ ID NO: 13935, and each strand having 12 to 30 nucleotides.

In some embodiments, the siRNA comprises a sense strand and an antisensestrand, the antisense strand being 100% complementary to a portion of anucleic acid having the nucleoside sequence of SEQ ID NO: 13936, andeach strand having 12 to 30 nucleotides. In some embodiments, the siRNAcomprises a sense strand and an antisense strand, the antisense strandbeing 100% complementary to a portion of a nucleic acid having thenucleoside sequence of SEQ ID NO: 13935, and each strand having 12 to 30nucleotides.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand is 14-30 nucleosides in length. In someembodiments, the composition comprises a sense strange that is at leastabout 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 nucleosides in length, or a range defined by anyof the two aforementioned numbers. In some embodiments, the compositioncomprises an antisense strand is 14-30 nucleosides in length. In someembodiments, the composition comprises an antisense strange that is atleast about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined byany of the two aforementioned numbers.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,each strand is independently about 14-30 nucleosides in length, and atleast one of the sense strand and the antisense strand comprises anucleoside sequence comprising about 14-30 contiguous nucleosides of afull-length human ANGPTL4 mRNA sequence such as SEQ ID NO: 13935. Insome embodiments, at least one of the sense strand and the antisensestrand comprise a nucleoside sequence comprising at least about 10, 11,12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, or more contiguous nucleosides of one of SEQ ID NO: 13935.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,each strand is independently about 14-30 nucleosides in length, and atleast one of the sense strand and the antisense strand comprises anucleoside sequence comprising about 14-30 contiguous nucleosides of afull-length human ANGPTL4 pre-mRNA sequence SEQ ID NO: 13936. In someembodiments, at least one of the sense strand and the antisense strandcomprise a nucleoside sequence comprising at least about 10, 11, 12, 13,14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, ormore contiguous nucleosides of one of SEQ ID NO: 13936.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand and the antisense strand form a double-strandedRNA duplex. In some embodiments, the first base pair of thedouble-stranded RNA duplex is an AU base pair.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, the sensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleicacid sequence thereof having 3 or 4 nucleoside substitutions, additions,or deletions. In some embodiments, the sense strand further comprises a3′ overhang. In some embodiments, the 3′ overhang comprises 1, 2, 3, 4,5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined byany two of the aforementioned numbers. In some embodiments, the 3′overhang comprises 1, 2, or more nucleosides. In some embodiments, the3′ overhang comprises 2 nucleosides. In some embodiments, the sensestrand further comprises a 5′ overhang. In some embodiments, the 5′overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or arange of nucleotides defined by any two of the aforementioned numbers.In some embodiments, the 5′ overhang comprises 1, 2, or morenucleosides. In some embodiments, the 5′ overhang comprises 2nucleosides. In some embodiments, the sense strand comprises anucleoside sequence comprising or consisting of the sequence of any oneof SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside additions at the 3′ end. The sequence of anyone of SEQ ID NOs: 1-1854 or 13970-13977 may include sequence of any oneof SEQ ID NOs: 1-1854. The sequence of any one of SEQ ID NOs: 1-1854 or13970-13977 may include sequence of any one of SEQ ID NOs: 13970-13977.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the antisense strand comprises a nucleoside sequence comprisingor consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, theantisense strand sequence comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 3 or 4 nucleosidesubstitutions, additions, or deletions. In some embodiments, theantisense strand further comprises a 3′ overhang. In some embodiments,the 3′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides,or a range of nucleotides defined by any two of the aforementionednumbers. In some embodiments, the 3′ overhang comprises 1, 2, or morenucleosides. In some embodiments, the 3′ overhang comprises 2nucleosides. In some embodiments, the antisense strand further comprisesa 5′ overhang. In some embodiments, the 5′ overhang comprises 1, 2, 3,4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides definedby any two of the aforementioned numbers. In some embodiments, the 5′overhang comprises 1, 2, or more nucleosides. In some embodiments, the5′ overhang comprises 2 nucleosides. In some embodiments, the antisensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985, or anucleic acid sequence thereof having 1 or 2 nucleoside additions at the3′ end. The sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985may include sequence of any one of SEQ ID NOs: 1855-3708. The sequenceof any one of SEQ ID NOs: 1855-3708 or 13978-13985 may include sequenceof any one of SEQ ID NOs: 13978-13985.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the antisense strand comprises a nucleoside sequence comprisingor consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the siRNA binds with a 19mer in a human ANGPTL4 mRNA. In someembodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a24mer, or a 25mer in a human ANGPTL4 mRNA.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the siRNA binds with a 17mer in a non-human primate ANGPTL4mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a22mer, a 23mer, a 24mer, or a 25mer in a non-human primate ANGPTL4 mRNA.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the siRNA binds with a 19mer in a human ANGPTL4 mRNA, or acombination thereof. In some embodiments, the siRNA binds with a 12mer,a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, and 18mer, a 19mer, a20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human ANGPTL4mRNA.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the siRNA binds with a human ANGPTL4 mRNA and less than or equalto 20 human off-targets, with no more than 2 mismatches in the antisensestrand. In some embodiments, the siRNA binds with a human ANGPTL4 mRNAand less than or equal to 10 human off-targets, with no more than 2mismatches in the antisense strand. In some embodiments, the siRNA bindswith a human ANGPTL4 mRNA and less than or equal to 30 humanoff-targets, with no more than 2 mismatches in the antisense strand. Insome embodiments, the siRNA binds with a human ANGPTL4 mRNA and lessthan or equal to 40 human off-targets, with no more than 2 mismatches inthe antisense strand. In some embodiments, the siRNA binds with a humanANGPTL4 mRNA and less than or equal to 50 human off-targets, with nomore than 2 mismatches in the antisense strand. In some embodiments, thesiRNA binds with a human ANGPTL4 mRNA and less than or equal to 10 humanoff-targets, with no more than 3 mismatches in the antisense strand. Insome embodiments, the siRNA binds with a human ANGPTL4 mRNA and lessthan or equal to 20 human off-targets, with no more than 3 mismatches inthe antisense strand. In some embodiments, the siRNA binds with a humanANGPTL4 mRNA and less than or equal to 30 human off-targets, with nomore than 3 mismatches in the antisense strand. In some embodiments, thesiRNA binds with a human ANGPTL4 mRNA and less than or equal to 40 humanoff-targets, with no more than 3 mismatches in the antisense strand. Insome embodiments, the siRNA binds with a human ANGPTL4 mRNA and lessthan or equal to 50 human off-targets, with no more than 3 mismatches inthe antisense strand.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,siRNA binds with a human ANGPTL4 mRNA target site that does not harboran SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos.2-18). In some embodiments, the MAF is greater or equal to about 2%,about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%,about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about16%, about 17%, about 18%, about 19%, or about 20%.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises the nucleoside sequence of any one ofSEQ ID NOs: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80,84, 111, 112, 116, 117, 118, 119, 120, 121, 125, 126, 127, 128, 129,149, 150, 152, 153, 154, 157, 158, 159, 161, 164, 165, 166, 167, 168,169, 172, 174, 175, 177, 196, 198, 199, 210, 211, 212, 214, 215, 216,217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245, 246, 250,252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280,282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329,330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352,353, 356, 377, 380, 382, 386, 388, 391, 392, 393, 394, 397, 398, 399,402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421, 422, 423,424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506, 509, 517,519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617,620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676, 677, 678,679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842,843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868, 871, 872,876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911, 912, 913,914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968, 1001, 1002,1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054,1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136,1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162,1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249,1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349,1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418,1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538,1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597,1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613, 1614, 1617,1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748,1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800,1801, 1802, or 1803, or a nucleic acid sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions; and/or the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 1886,1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918,1933, 1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979,1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007, 2008, 2011, 2012, 2013,2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050,2052, 2053, 2064, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075,2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107,2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134,2136, 2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180,2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196,2201, 2203, 2204, 2206, 2207, 2210, 2231, 2234, 2236, 2240, 2242, 2245,2246, 2247, 2248, 2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267,2268, 2269, 2271, 2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281,2282, 2283, 2284, 2285, 2289, 2335, 2338, 2360, 2363, 2371, 2373, 2374,2419, 2424, 2425, 2426, 2443, 2461, 2462, 2464, 2465, 2466, 2470, 2471,2474, 2477, 2489, 2491, 2494, 2497, 2507, 2526, 2527, 2528, 2529, 2530,2531, 2532, 2533, 2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546, 2549,2684, 2688, 2695, 2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710,2711, 2713, 2720, 2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746, 2747,2748, 2751, 2754, 2756, 2761, 2765, 2766, 2767, 2768, 2769, 2770, 2771,2772, 2773, 2774, 2775, 2776, 2779, 2799, 2822, 2855, 2856, 2859, 2860,2863, 2864, 2865, 2867, 2882, 2886, 2891, 2906, 2907, 2908, 2909, 2911,2912, 2918, 2966, 2976, 2978, 2980, 2981, 2987, 2988, 2990, 2991, 3001,3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018,3019, 3020, 3025, 3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106, 3107,3113, 3130, 3139, 3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205,3206, 3232, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284,3302, 3331, 3341, 3342, 3343, 3347, 3348, 3373, 3377, 3392, 3410, 3415,3417, 3418, 3419, 3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455,3456, 3457, 3458, 3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 3553,3555, 3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605,3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656,or 3657, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises the nucleoside sequence of any one ofSEQ ID NOs: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80,84, 111, 112, 116, 117, 118, 119, 120, 121, 125, 126, 127, 128, 129,149, 150, 152, 153, 154, 157, 158, 159, 161, 164, 165, 166, 167, 168,169, 172, 174, 175, 177, 196, 198, 199, 210, 211, 212, 214, 215, 216,217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245, 246, 250,252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280,282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329,330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352,353, 356, 377, 380, 382, 386, 388, 391, 392, 393, 394, 397, 398, 399,402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421, 422, 423,424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506, 509, 517,519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617,620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676, 677, 678,679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842,843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868, 871, 872,876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911, 912, 913,914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968, 1001, 1002,1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054,1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136,1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162,1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249,1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349,1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418,1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538,1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597,1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613, 1614, 1617,1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748,1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800,1801, 1802, or 1803; and/or the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1886, 1887, 1888, 1889,1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1938,1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982,1983, 2003, 2004, 2006, 2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019,2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064,2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075, 2076, 2077, 2082,2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107, 2108, 2109, 2114,2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134, 2136, 2143, 2144,2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184,2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2204,2206, 2207, 2210, 2231, 2234, 2236, 2240, 2242, 2245, 2246, 2247, 2248,2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267, 2268, 2269, 2271,2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284,2285, 2289, 2335, 2338, 2360, 2363, 2371, 2373, 2374, 2419, 2424, 2425,2426, 2443, 2461, 2462, 2464, 2465, 2466, 2470, 2471, 2474, 2477, 2489,2491, 2494, 2497, 2507, 2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533,2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546, 2549, 2684, 2688, 2695,2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710, 2711, 2713, 2720,2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746, 2747, 2748, 2751, 2754,2756, 2761, 2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774,2775, 2776, 2779, 2799, 2822, 2855, 2856, 2859, 2860, 2863, 2864, 2865,2867, 2882, 2886, 2891, 2906, 2907, 2908, 2909, 2911, 2912, 2918, 2966,2976, 2978, 2980, 2981, 2987, 2988, 2990, 2991, 3001, 3002, 3003, 3005,3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025,3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106, 3107, 3113, 3130, 3139,3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259,3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341,3342, 3343, 3347, 3348, 3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419,3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458,3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 3553, 3555, 3556, 3557,3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633,3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656, or 3657.

In some embodiments, the sense strand comprises the nucleoside sequenceof any one of SEQ ID NOs: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62,63, 64, 79, 80, 84, 111, 112, 116, 117, 118, 119, 120, 121, 125, 126,127, 128, 129, 149, 150, 152, 153, 154, 157, 158, 159, 161, 164, 165,166, 167, 168, 169, 172, 174, 175, 177, 196, 198, 199, 210, 211, 212,214, 215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241,245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271,272, 274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325,326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347,349, 350, 352, 353, 356, 377, 380, 382, 386, 388, 391, 392, 393, 394,397, 398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420,421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484,506, 509, 517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611,612, 616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675,676, 677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830,834, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866,868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907,911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945,968, 1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037,1052, 1053, 1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127,1133, 1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157,1158, 1161, 1162, 1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182,1184, 1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343,1347, 1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415,1416, 1417, 1418, 1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494,1519, 1523, 1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580,1581, 1589, 1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611,1613, 1614, 1617, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742,1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788,1798, 1799, 1800, 1801, 1802, or 1803, or a nucleic acid sequencethereof having 1 or 2 nucleoside additions at the 3′ end. In someembodiments, the antisense strand comprises the nucleoside sequence ofany one of SEQ ID NOs: 1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912,1913, 1915, 1916, 1917, 1918, 1933, 1934, 1938, 1965, 1966, 1970, 1971,1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006,2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023,2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066, 2068, 2069,2070, 2071, 2072, 2073, 2075, 2076, 2077, 2082, 2084, 2085, 2094, 2095,2099, 2100, 2104, 2106, 2107, 2108, 2109, 2114, 2115, 2116, 2117, 2119,2120, 2125, 2126, 2128, 2134, 2136, 2143, 2144, 2145, 2146, 2147, 2153,2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188,2189, 2191, 2192, 2193, 2196, 2201, 2203, 2204, 2206, 2207, 2210, 2231,2234, 2236, 2240, 2242, 2245, 2246, 2247, 2248, 2251, 2252, 2253, 2256,2258, 2259, 2265, 2266, 2267, 2268, 2269, 2271, 2273, 2274, 2275, 2276,2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285, 2289, 2335, 2338,2360, 2363, 2371, 2373, 2374, 2419, 2424, 2425, 2426, 2443, 2461, 2462,2464, 2465, 2466, 2470, 2471, 2474, 2477, 2489, 2491, 2494, 2497, 2507,2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533, 2535, 2536, 2537, 2538,2540, 2541, 2543, 2546, 2549, 2684, 2688, 2695, 2696, 2697, 2698, 2704,2705, 2706, 2707, 2708, 2710, 2711, 2713, 2720, 2722, 2725, 2726, 2730,2741, 2742, 2744, 2746, 2747, 2748, 2751, 2754, 2756, 2761, 2765, 2766,2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774, 2775, 2776, 2779, 2799,2822, 2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882, 2886, 2891,2906, 2907, 2908, 2909, 2911, 2912, 2918, 2966, 2976, 2978, 2980, 2981,2987, 2988, 2990, 2991, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011,3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029, 3035, 3036,3038, 3102, 3103, 3106, 3107, 3113, 3130, 3139, 3164, 3169, 3192, 3197,3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267, 3268, 3269,3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341, 3342, 3343, 3347, 3348,3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425, 3426, 3434,3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458, 3459, 3460, 3464, 3465,3467, 3468, 3471, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595, 3596,3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642,3652, 3653, 3654, 3655, 3656, or 3657, or a nucleic acid sequencethereof having 1 or 2 nucleoside additions at the 3′ end. For example,the nucleic acid sequence may have 2 uracil nucleoside additions at the3′ end. The nucleic acid sequence may have 1 uracil nucleoside additionat the 3′ end. The nucleic acid sequence may have more than 2 nucleosideadditions at the 3′ end.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises the nucleoside sequence of any one ofSEQ ID NOs: 33, 34, 35, 36, 56, 121, 272, 280, 282, 289, 290, 291, 292,293, 321, 323, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338,339, 342, 347, 349, 411, 412, 430, 431, 435, 481, 484, 509, 517, 519,520, 565, 620, 635, 637, 640, 830, 834, 841, 842, 843, 844, 850, 871,872, 876, 887, 888, 894, 897, 902, 945, 1001, 1002, 1005, 1037, 1133,1134, 1137, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164,1165, 1166, 1171, 1172, 1248, 1249, 1315, 1338, 1343, 1347, 1348, 1429,1430, 1570, 1571, 1572, 1610, 1611, 1617, 1780, 1784, or 1787; and/orthe antisense strand comprises the nucleoside sequence of any one of SEQID NOs: 1887, 1888, 1889, 1890, 1910, 1975, 2126, 2134, 2136, 2143,2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186,2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284,2285, 2289, 2335, 2338, 2363, 2371, 2373, 2374, 2419, 2474, 2489, 2491,2494, 2684, 2688, 2695, 2696, 2697, 2698, 2704, 2725, 2726, 2730, 2741,2742, 2748, 2751, 2756, 2799, 2855, 2856, 2859, 2891, 2987, 2988, 2991,3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020,3025, 3026, 3102, 3103, 3169, 3192, 3197, 3201, 3202, 3283, 3284, 3424,3425, 3426, 3464, 3465, 3471, 3634, 3638, or 3641.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises the nucleoside sequence of any one ofSEQ ID NOs: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80,112, 116, 117, 118, 119, 120, 125, 126, 127, 128, 129, 149, 150, 152,153, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175,196, 199, 211, 212, 214, 215, 216, 217, 218, 219, 221, 222, 223, 228,230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262,263, 265, 266, 271, 272, 274, 280, 289, 290, 291, 292, 293, 299, 304,321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338,339, 342, 347, 349, 350, 352, 353, 356, 380, 382, 386, 388, 391, 392,393, 394, 397, 398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 420,421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 484, 517,519, 520, 565, 570, 571, 572, 607, 608, 610, 611, 612, 616, 617, 620,635, 637, 640, 672, 673, 674, 675, 676, 677, 678, 679, 681, 682, 683,684, 686, 687, 689, 692, 695, 830, 841, 842, 843, 844, 850, 851, 852,853, 854, 856, 857, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893,894, 902, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922,945, 1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1052,1053, 1054, 1055, 1057, 1058, 1112, 1122, 1124, 1126, 1127, 1133, 1134,1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164,1165, 1166, 1175, 1182, 1184, 1252, 1253, 1259, 1276, 1285, 1310, 1315,1343, 1347, 1348, 1349, 1350, 1351, 1405, 1407, 1413, 1414, 1415, 1416,1417, 1418, 1429, 1430, 1448, 1519, 1523, 1556, 1561, 1563, 1564, 1565,1571, 1572, 1580, 1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606,1611, 1613, 1614, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742,1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1788, 1798,1799, 1801, 1802, or 1803; and/or the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1886, 1887, 1888, 1889,1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1966,1970, 1971, 1972, 1973, 1974, 1979, 1980, 1981, 1982, 1983, 2003, 2004,2006, 2007, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023,2026, 2028, 2029, 2050, 2053, 2065, 2066, 2068, 2069, 2070, 2071, 2072,2073, 2075, 2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104,2106, 2107, 2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126,2128, 2134, 2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179,2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193,2196, 2201, 2203, 2204, 2206, 2207, 2210, 2234, 2236, 2240, 2242, 2245,2246, 2247, 2248, 2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267,2268, 2269, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283,2284, 2285, 2289, 2338, 2371, 2373, 2374, 2419, 2424, 2425, 2426, 2461,2462, 2464, 2465, 2466, 2470, 2471, 2474, 2489, 2491, 2494, 2526, 2527,2528, 2529, 2530, 2531, 2532, 2533, 2535, 2536, 2537, 2538, 2540, 2541,2543, 2546, 2549, 2684, 2695, 2696, 2697, 2698, 2704, 2705, 2706, 2707,2708, 2710, 2711, 2720, 2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746,2747, 2748, 2756, 2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773,2774, 2775, 2776, 2799, 2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867,2882, 2886, 2906, 2907, 2908, 2909, 2911, 2912, 2966, 2976, 2978, 2980,2981, 2987, 2988, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012,3015, 3016, 3018, 3019, 3020, 3029, 3036, 3038, 3106, 3107, 3113, 3130,3139, 3164, 3169, 3197, 3201, 3202, 3203, 3204, 3205, 3259, 3261, 3267,3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3373, 3377, 3410, 3415,3417, 3418, 3419, 3425, 3426, 3434, 3435, 3443, 3451, 3455, 3456, 3457,3458, 3459, 3460, 3465, 3467, 3468, 3547, 3553, 3555, 3556, 3557, 3576,3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634,3638, 3642, 3652, 3653, 3655, 3656, or 3657.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises the nucleoside sequence of any one ofSEQ ID NOs: 33, 34, 35, 36, 56, 272, 280, 289, 290, 291, 292, 293, 321,323, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342,347, 349, 411, 412, 430, 431, 435, 484, 517, 519, 520, 565, 620, 635,637, 640, 830, 841, 842, 843, 844, 850, 871, 872, 876, 887, 888, 894,902, 945, 1001, 1002, 1005, 1133, 1134, 1149, 1151, 1153, 1154, 1155,1157, 1158, 1161, 1162, 1164, 1165, 1166, 1315, 1343, 1347, 1348, 1429,1430, 1571, 1572, 1611, 1780, or 1784; and/or the antisense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 1887, 1888,1889, 1890, 1910, 2126, 2134, 2143, 2144, 2145, 2146, 2147, 2175, 2177,2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193,2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2338, 2371, 2373, 2374,2419, 2474, 2489, 2491, 2494, 2684, 2695, 2696, 2697, 2698, 2704, 2725,2726, 2730, 2741, 2742, 2748, 2756, 2799, 2855, 2856, 2859, 2987, 2988,3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020,3169, 3197, 3201, 3202, 3283, 3284, 3425, 3426, 3465, 3634, or 3638.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises the nucleoside sequence of any one ofSEQ ID NOs: 32, 36, 56, 57, 58, 61, 62, 79, 80, 117, 119, 125, 126, 128,149, 152, 157, 158, 159, 161, 165, 166, 167, 168, 169, 174, 196, 211,212, 217, 218, 219, 230, 231, 245, 246, 253, 260, 261, 262, 271, 272,280, 289, 291, 292, 293, 304, 321, 323, 325, 326, 328, 330, 331, 332,333, 334, 337, 338, 342, 347, 349, 352, 353, 356, 380, 382, 386, 388,391, 392, 394, 399, 413, 414, 415, 422, 423, 424, 425, 426, 435, 517,519, 520, 565, 571, 607, 608, 612, 617, 620, 635, 640, 672, 673, 674,675, 678, 679, 681, 683, 684, 687, 692, 842, 843, 850, 851, 854, 866,868, 876, 892, 893, 902, 911, 912, 913, 914, 916, 919, 945, 1001, 1002,1006, 1010, 1028, 1052, 1053, 1054, 1055, 1057, 1112, 1124, 1127, 1147,1149, 1151, 1153, 1155, 1157, 1164, 1175, 1182, 1184, 1259, 1276, 1285,1315, 1343, 1349, 1350, 1351, 1405, 1407, 1413, 1415, 1418, 1564, 1571,1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1613, 1614, 1693,1701, 1722, 1740, 1745, 1751, 1755, 1801, 1802, or 1803, or 3638; and/orthe antisense strand comprises the nucleoside sequence of any one of SEQID NOs: 1886, 1890, 1910, 1911, 1912, 1915, 1916, 1933, 1934, 1971,1973, 1979, 1980, 1982, 2003, 2006, 2011, 2012, 2013, 2015, 2019, 2020,2021, 2022, 2023, 2028, 2050, 2065, 2066, 2071, 2072, 2073, 2084, 2085,2099, 2100, 2107, 2114, 2115, 2116, 2125, 2126, 2134, 2143, 2145, 2146,2147, 2158, 2175, 2177, 2179, 2180, 2182, 2184, 2185, 2186, 2187, 2188,2191, 2192, 2196, 2201, 2203, 2206, 2207, 2210, 2234, 2236, 2240, 2242,2245, 2246, 2248, 2253, 2267, 2268, 2269, 2276, 2277, 2278, 2279, 2280,2289, 2371, 2373, 2374, 2419, 2425, 2461, 2462, 2466, 2471, 2474, 2489,2494, 2526, 2527, 2528, 2529, 2532, 2533, 2535, 2537, 2538, 2541, 2546,2696, 2697, 2704, 2705, 2708, 2720, 2722, 2730, 2746, 2747, 2756, 2765,2766, 2767, 2768, 2770, 2773, 2799, 2855, 2856, 2860, 2864, 2882, 2906,2907, 2908, 2909, 2911, 2966, 2978, 2981, 3001, 3003, 3005, 3007, 3009,3011, 3018, 3029, 3036, 3038, 3113, 3130, 3139, 3169, 3197, 3203, 3204,3205, 3259, 3261, 3267, 3269, 3272, 3418, 3425, 3435, 3443, 3451, 3455,3456, 3457, 3458, 3459, 3460, 3467, 3468, 3547, 3555, 3576, 3594, 3599,3605, 3609, 3655, 3656, or 3657.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,the sense strand comprises the nucleoside sequence of any one of SEQ ID36, 56, 272, 280, 289, 291, 292, 293, 321, 323, 326, 328, 330, 331, 332,333, 334, 337, 338, 342, 347, 349, 435, 517, 519, 520, 565, 620, 635,640, 842, 843, 850, 876, 902, 945, 1001, 1002, 1149, 1151, 1153, 1155,1157, 1164, 1315, 1343, or 1571; and/or the antisense strand comprisesthe nucleoside sequence of any one of SEQ ID 1890, 1910, 2126, 2134,2143, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2184, 2185, 2186, 2187,2188, 2191, 2192, 2196, 2201, 2203, 2289, 2371, 2373, 2374, 2419, 2474,2489, 2494, 2696, 2697, 2704, 2730, 2756, 2799, 2855, 2856, 3003, 3005,3007, 3009, 3011, 3018, 3169, 3197, or 3425.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises the nucleoside sequence of any one ofSEQ ID NOs: 32, 36, 56, 58, 61, 62, 80, 117, 119, 126, 152, 154, 157,158, 159, 161, 166, 169, 174, 177, 196, 211, 212, 217, 218, 230, 231,245, 253, 260, 261, 271, 272, 280, 289, 293, 304, 328, 330, 331, 332,333, 334, 337, 342, 347, 349, 353, 356, 386, 388, 391, 392, 394, 414,415, 422, 423, 424, 426, 435, 520, 571, 608, 612, 617, 653, 672, 678,679, 681, 683, 692, 842, 843, 851, 854, 859, 876, 892, 900, 913, 914,919, 968, 1001, 1002, 1054, 1057, 1064, 1112, 1124, 1157, 1164, 1182,1184, 1248, 1259, 1343, 1351, 1352, 1415, 1418, 1564, 1581, 1602, 1614,1693, 1701, 1722, 1740, 1751, 1755, or 1787; and/or the antisense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 1886, 1890,1910, 1912, 1915, 1916, 1934, 1971, 1973, 1980, 2006, 2008, 2011, 2012,2013, 2015, 2020, 2023, 2028, 2031, 2050, 2065, 2066, 2071, 2072, 2084,2085, 2099, 2107, 2114, 2115, 2125, 2126, 2134, 2143, 2147, 2158, 2182,2184, 2185, 2186, 2187, 2188, 2191, 2196, 2201, 2203, 2207, 2210, 2240,2242, 2245, 2246, 2248, 2268, 2269, 2276, 2277, 2278, 2280, 2289, 2374,2425, 2462, 2466, 2471, 2507, 2526, 2532, 2533, 2535, 2537, 2546, 2696,2697, 2705, 2708, 2713, 2730, 2746, 2754, 2767, 2768, 2773, 2822, 2855,2856, 2908, 2911, 2918, 2966, 2978, 3011, 3018, 3036, 3038, 3102, 3113,3197, 3205, 3206, 3269, 3272, 3418, 3435, 3456, 3468, 3547, 3555, 3576,3594, 3605, 3609, or 3641.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the sense strand comprises the nucleoside sequence of any one ofSEQ ID NOs: 36, 56, 272, 280, 289, 293, 328, 330, 331, 332, 333, 334,337, 342, 347, 349, 435, 520, 842, 843, 876, 1001, 1002, 1157, 1164, or1343; and/or the antisense strand comprises the nucleoside sequence ofany one of SEQ ID NOs: 1890, 1910, 2126, 2134, 2143, 2147, 2182, 2184,2185, 2186, 2187, 2188, 2191, 2196, 2201, 2203, 2289, 2374, 2696, 2697,2730, 2855, 2856, 3011, 3018, or 3197.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA of subset A, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA of subset A, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA of subsetA. In some embodiments, the siRNA is cross-reactive with a non-humanprimate (NHP) ANGPTL4 mRNA. The siRNA may include one or moreinternucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA in Table 4, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA in Table 4, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA in Table4. In some embodiments, the siRNA is cross-reactive with a non-humanprimate (NHP) ANGPTL4 mRNA. The siRNA may include one or moreinternucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA of subset B, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA of subset B, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA of subsetB. In some embodiments, the siRNA is cross-reactive with a non-humanprimate (NHP) ANGPTL4 mRNA. The siRNA may include one or moreinternucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA of subset C, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA of subset C, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA of subsetC. In some embodiments, the siRNA is cross-reactive with a non-humanprimate (NHP) ANGPTL4 mRNA. The siRNA may include one or moreinternucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA of subset D, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA of subset D, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA of subsetD. In some embodiments, the siRNA is cross-reactive with a non-humanprimate (NHP) ANGPTL4 mRNA. The siRNA may include one or moreinternucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA of subset E, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA of subset E, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA of subsetE. In some embodiments, the siRNA is cross-reactive with a non-humanprimate (NHP) ANGPTL4 mRNA. The siRNA may include one or moreinternucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA of subset F, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA of subset F, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA of subsetF. In some embodiments, the siRNA is cross-reactive with a non-humanprimate (NHP) ANGPTL4 mRNA. The siRNA may include one or moreinternucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA of subset G, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA of subset G, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA of subsetG. In some embodiments, the siRNA is cross-reactive with a non-humanprimate (NHP) ANGPTL4 mRNA. The siRNA may include one or moreinternucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA in Table 5, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA in Table 5, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA in Table5. In some embodiments, the siRNA comprises one or more of theinternucleoside linkages and/or nucleoside modifications of the siRNA inTable 5. In some embodiments, the siRNA comprises the internucleosidelinkages and/or nucleoside modifications of the siRNA in Table 5. Insome embodiments, the siRNA is unmodified. In some embodiments, thesense strand sequence of an siRNA in Table 5 comprises modificationpattern 1S. In some embodiments, the sense strand sequence of an siRNAin Table 5 comprises modification pattern 3S or 6S. In some embodiments,the sense strand sequence of an siRNA in Table 5 comprises modificationpattern 1AS. In some embodiments, the sense strand sequence of an siRNAin Table 5 comprises modification pattern 4AS, 5AS, 7AS, or 8AS.

In some embodiments, the siRNA reduces an ANGPTL mRNA measurement by 10%or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% ormore, 70% or more, 80% or more, or 90% or more, relative to a control.In some embodiments, the siRNA reduces an ANGPTL mRNA measurement by 10%or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% orless, 70% or less, 80% or less, or 90% or less, relative to a control.In some embodiments, the reduction is in a cell line such as U-138 MGcells. In some embodiments, the reduction is in response to 1 nM of thesiRNA. In some embodiments, the reduction is in response to 10 nM of thesiRNA.

Some siRNAs in Table 5 reduced an ANGPTL mRNA measurement by 10% ormore, relative to a control. In some embodiments, the siRNA comprisesthe sense strand and/or the antisense strand sequence of ETD00646,ETD00648, ETD00649, ETD00651, ETD00653, ETD00654, ETD00655, ETD00656,ETD00658, ETD00660, ETD00661, ETD00662, ETD00667, ETD00669, ETD00683,ETD00684, ETD00686, ETD00688, ETD00689, ETD00691, ETD00692, ETD00694,ETD00702, ETD00709, ETD00713, ETD00714, ETD00715, ETD00716, ETD00717,ETD00719, ETD00721, ETD00726, ETD00727, ETD00728, ETD00729, ETD00730,ETD00731, ETD00733, ETD00736, ETD00738, or ETD00743, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of ETD00646, ETD00648, ETD00649,ETD00651, ETD00653, ETD00654, ETD00655, ETD00656, ETD00658, ETD00660,ETD00661, ETD00662, ETD00667, ETD00669, ETD00683, ETD00684, ETD00686,ETD00688, ETD00689, ETD00691, ETD00692, ETD00694, ETD00702, ETD00709,ETD00713, ETD00714, ETD00715, ETD00716, ETD00717, ETD00719, ETD00721,ETD00726, ETD00727, ETD00728, ETD00729, ETD00730, ETD00731, ETD00733,ETD00736, ETD00738, or ETD00743, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA comprises the sense strand and/or the antisensestrand sequence of ETD00646, ETD00648, ETD00649, ETD00651, ETD00653,ETD00654, ETD00655, ETD00656, ETD00658, ETD00660, ETD00661, ETD00662,ETD00667, ETD00669, ETD00683, ETD00684, ETD00686, ETD00688, ETD00689,ETD00691, ETD00692, ETD00694, ETD00702, ETD00709, ETD00713, ETD00714,ETD00715, ETD00716, ETD00717, ETD00719, ETD00721, ETD00726, ETD00727,ETD00728, ETD00729, ETD00730, ETD00731, ETD00733, ETD00736, ETD00738, orETD00743. In some embodiments, the siRNA comprises one or more of theinternucleoside linkages and/or nucleoside modifications of ETD00646,ETD00648, ETD00649, ETD00651, ETD00653, ETD00654, ETD00655, ETD00656,ETD00658, ETD00660, ETD00661, ETD00662, ETD00667, ETD00669, ETD00683,ETD00684, ETD00686, ETD00688, ETD00689, ETD00691, ETD00692, ETD00694,ETD00702, ETD00709, ETD00713, ETD00714, ETD00715, ETD00716, ETD00717,ETD00719, ETD00721, ETD00726, ETD00727, ETD00728, ETD00729, ETD00730,ETD00731, ETD00733, ETD00736, ETD00738, or ETD00743. In someembodiments, the siRNA comprises the internucleoside linkages and/ornucleoside modifications of ETD00646, ETD00648, ETD00649, ETD00651,ETD00653, ETD00654, ETD00655, ETD00656, ETD00658, ETD00660, ETD00661,ETD00662, ETD00667, ETD00669, ETD00683, ETD00684, ETD00686, ETD00688,ETD00689, ETD00691, ETD00692, ETD00694, ETD00702, ETD00709, ETD00713,ETD00714, ETD00715, ETD00716, ETD00717, ETD00719, ETD00721, ETD00726,ETD00727, ETD00728, ETD00729, ETD00730, ETD00731, ETD00733, ETD00736,ETD00738, or ETD00743. In some embodiments, the siRNA is unmodified.

The siRNA may comprise an unmodified version of a sense strand sequenceof an siRNA listed in Table 5. In some embodiments, the siRNA of listedin Table 5 comprises any sense strand sequence of a subset A siRNA thatis cross-reactive with a NHP ANGPTL4 mRNA. The siRNA may comprise anunmodified version of an antisense strand sequence of an siRNA listed inTable 5. In some embodiments, the siRNA of listed in Table 5 comprisesany antisense strand sequence of a subset A siRNA that is cross-reactivewith a NHP ANGPTL4 mRNA.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA in Table 6, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA in Table 6, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA in Table6. In some embodiments, the siRNA comprises one or more of theinternucleoside linkages and/or nucleoside modifications of the siRNA inTable 6. In some embodiments, the siRNA comprises the internucleosidelinkages and/or nucleoside modifications of the siRNA in Table 6. Insome embodiments, the siRNA is unmodified.

The siRNA may comprise an unmodified version of an antisense strandsequence of an siRNA listed in Table 6. In some embodiments, the siRNAcomprises the sense strand sequence of SEQ ID NO: 32, 570, 571, 572,589, 607, 759, 801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589,1597, 1702, 1840, or 1842, or a nucleic acid sequence thereof having 3or 4 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA comprises the sense strand sequence of SEQ ID NO:32, 570, 571, 572, 589, 607, 759, 801, 1276, 1285, 1489, 1490, 1564,1580, 1581, 1589, 1597, 1702, 1840, or 1842, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions.In some embodiments, the siRNA comprises the sense strand sequence ofSEQ ID NO: 32, 570, 571, 572, 589, 607, 759, 801, 1276, 1285, 1489,1490, 1564, 1580, 1581, 1589, 1597, 1702, 1840, or 1842. The siRNA mayinclude the sense strand sequence of SEQ ID NO: 32, 570, 571, 572, 589,607, 759, 801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597,1702, 1840, or 1842, and one or more internucleoside linkages and/or oneor more nucleoside modifications. The siRNA may include the sense strandsequence of SEQ ID NO: 32, 570, 571, 572, 589, 607, 759, 801, 1276,1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1702, 1840, or 1842, anda modification pattern described herein. For example, any of the sensestrands comprising the sequence of SEQ ID NO: 32, 570, 571, 572, 589,607, 759, 801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597,1702, 1840, or 1842 may in some cases comprise modification pattern 1S,2S, 3S, or 6S.

The siRNA may comprise an unmodified version of an antisense strandsequence of an siRNA listed in Table 6. In some embodiments, the siRNAcomprises the antisense strand sequence of SEQ ID NO: 1886, 2424, 2425,2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343, 3344, 3418, 3434, 3435,3443, 3451, 3556, 3694, or 3696, or a nucleic acid sequence thereofhaving 3 or 4 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA comprises the antisense strand sequence of SEQ IDNO: 1886, 2424, 2425, 2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343,3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694, or 3696, or a nucleicacid sequence thereof having 1 or 2 nucleoside substitutions, additions,or deletions. In some embodiments, the siRNA comprises the antisensestrand sequence of SEQ ID NO: 1886, 2424, 2425, 2426, 2443, 2461, 2613,2655, 3130, 3139, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694,or 3696. The siRNA may include the antisense strand sequence of SEQ IDNO: 1886, 2424, 2425, 2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343,3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694, or 3696, and one or moreintemucleoside linkages and/or one or more nucleoside modifications. ThesiRNA may include the antisense strand sequence of SEQ ID NO: 1886,2424, 2425, 2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343, 3344, 3418,3434, 3435, 3443, 3451, 3556, 3694, or 3696, and a modification patterndescribed herein. For example, any of the antisense strands comprisingthe sequence of SEQ ID NO: 1886, 2424, 2425, 2426, 2443, 2461, 2613,2655, 3130, 3139, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694,or 3696 may comprise modification pattern 1AS, 3AS, 4AS, 5AS, 7AS, or8AS.

Some siRNAs in Table 6 reduced an ANGPTL mRNA measurement by 10% ormore, relative to a control. In some embodiments, the siRNA comprisesthe sense strand and/or the antisense strand sequence of ETD00915,ETD00916, ETD00917, ETD00921, ETD00924, ETD00925, ETD00926, ETD00927,ETD00928, ETD00929, ETD00930, ETD00931, ETD00932, ETD00933, or ETD00934,or a nucleic acid sequence thereof having 3 or 4 nucleosidesubstitutions, additions, or deletions. In some embodiments, the siRNAcomprises the sense strand and/or the antisense strand sequence ofETD00915, ETD00916, ETD00917, ETD00921, ETD00924, ETD00925, ETD00926,ETD00927, ETD00928, ETD00929, ETD00930, ETD00931, ETD00932, ETD00933, orETD00934, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions. In some embodiments, the siRNAcomprises the sense strand and/or the antisense strand sequence ofETD00915, ETD00916, ETD00917, ETD00921, ETD00924, ETD00925, ETD00926,ETD00927, ETD00928, ETD00929, ETD00930, ETD00931, ETD00932, ETD00933, orETD00934. In some embodiments, the siRNA comprises one or more of theinternucleoside linkages and/or nucleoside modifications of ETD00915,ETD00916, ETD00917, ETD00921, ETD00924, ETD00925, ETD00926, ETD00927,ETD00928, ETD00929, ETD00930, ETD00931, ETD00932, ETD00933, or ETD00934.In some embodiments, the siRNA comprises the internucleoside linkagesand/or nucleoside modifications of ETD00915, ETD00916, ETD00917,ETD00921, ETD00924, ETD00925, ETD00926, ETD00927, ETD00928, ETD00929,ETD00930, ETD00931, ETD00932, ETD00933, or ETD00934. In someembodiments, the siRNA is unmodified.

The siRNA may comprise a sense strand sequence of an siRNA that reducedan ANGPTL mRNA measurement by 10% or more, relative to a control, inTable 5 or Table 6. In some embodiments, the siRNA comprises the sensestrand sequence of any one of SEQ ID NOS: 14012, 14014, 14015, 14017,14019, 14020, 14021, 14022, 14024, 14026, 14027, 14028, 14033, 14035,14049, 14050, 14052, 14054, 14055, 14057, 14058, 14060, 14068, 14075,14079, 14080, 14081, 14082, 14083, 14085, 14087, 14092, 14093, 14094,14095, 14096, 14097, 14099, 14102, 14104, 14109, 14114, 14115, 14116,14120, 14123, 14124, 14125, 14126, 14127, 14128, 14129, 14130, 14131,14132, or 14133, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA comprises the sense strand sequence of any one of SEQ ID NOS:14012, 14014, 14015, 14017, 14019, 14020, 14021, 14022, 14024, 14026,14027, 14028, 14033, 14035, 14049, 14050, 14052, 14054, 14055, 14057,14058, 14060, 14068, 14075, 14079, 14080, 14081, 14082, 14083, 14085,14087, 14092, 14093, 14094, 14095, 14096, 14097, 14099, 14102, 14104,14109, 14114, 14115, 14116, 14120, 14123, 14124, 14125, 14126, 14127,14128, 14129, 14130, 14131, 14132, or 14133, ora nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions.In some embodiments, the siRNA comprises the sense strand sequence ofany one of SEQ ID NOS: 14012, 14014, 14015, 14017, 14019, 14020, 14021,14022, 14024, 14026, 14027, 14028, 14033, 14035, 14049, 14050, 14052,14054, 14055, 14057, 14058, 14060, 14068, 14075, 14079, 14080, 14081,14082, 14083, 14085, 14087, 14092, 14093, 14094, 14095, 14096, 14097,14099, 14102, 14104, 14109, 14114, 14115, 14116, 14120, 14123, 14124,14125, 14126, 14127, 14128, 14129, 14130, 14131, 14132, or 14133. Insome embodiments, the siRNA comprises one or more of the internucleosidelinkages and/or nucleoside modifications of the sense strand of 14012,14014, 14015, 14017, 14019, 14020, 14021, 14022, 14024, 14026, 14027,14028, 14033, 14035, 14049, 14050, 14052, 14054, 14055, 14057, 14058,14060, 14068, 14075, 14079, 14080, 14081, 14082, 14083, 14085, 14087,14092, 14093, 14094, 14095, 14096, 14097, 14099, 14102, 14104, 14109,14114, 14115, 14116, 14120, 14123, 14124, 14125, 14126, 14127, 14128,14129, 14130, 14131, 14132, or 14133. In some embodiments, the siRNAcomprises the internucleoside linkages and/or nucleoside modificationsof the sense strand of 14012, 14014, 14015, 14017, 14019, 14020, 14021,14022, 14024, 14026, 14027, 14028, 14033, 14035, 14049, 14050, 14052,14054, 14055, 14057, 14058, 14060, 14068, 14075, 14079, 14080, 14081,14082, 14083, 14085, 14087, 14092, 14093, 14094, 14095, 14096, 14097,14099, 14102, 14104, 14109, 14114, 14115, 14116, 14120, 14123, 14124,14125, 14126, 14127, 14128, 14129, 14130, 14131, 14132, or 14133. Insome embodiments, the siRNA is unmodified.

The siRNA may comprise an antisense strand sequence of an siRNA thatreduced an ANGPTL mRNA measurement by 10% or more, relative to acontrol, in Table 5 or Table 6. In some embodiments, the siRNA comprisesthe antisense strand sequence of any one of SEQ ID NOS: 14167, 14169,14170, 14172, 14174, 14175, 14176, 14177, 14179, 14181, 14182, 14183,14188, 14190, 14204, 14205, 14207, 14209, 14210, 14212, 14213, 14215,14223, 14230, 14234, 14235, 14236, 14237, 14238, 14240, 14242, 14247,14248, 14249, 14250, 14251, 14252, 14254, 14257, 14259, 14264, 14269,14270, 14271, 14275, 14278, 14279, 14280, 14281, 14282, 14283, 14284,14285, 14286, 14287, or 14288, or a nucleic acid sequence thereof having3 or 4 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA comprises the antisense strand sequence of anyone of SEQ ID NOS: 14167, 14169, 14170, 14172, 14174, 14175, 14176,14177, 14179, 14181, 14182, 14183, 14188, 14190, 14204, 14205, 14207,14209, 14210, 14212, 14213, 14215, 14223, 14230, 14234, 14235, 14236,14237, 14238, 14240, 14242, 14247, 14248, 14249, 14250, 14251, 14252,14254, 14257, 14259, 14264, 14269, 14270, 14271, 14275, 14278, 14279,14280, 14281, 14282, 14283, 14284, 14285, 14286, 14287, or 14288, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises theantisense strand sequence of any one of SEQ ID NOS: 14167, 14169, 14170,14172, 14174, 14175, 14176, 14177, 14179, 14181, 14182, 14183, 14188,14190, 14204, 14205, 14207, 14209, 14210, 14212, 14213, 14215, 14223,14230, 14234, 14235, 14236, 14237, 14238, 14240, 14242, 14247, 14248,14249, 14250, 14251, 14252, 14254, 14257, 14259, 14264, 14269, 14270,14271, 14275, 14278, 14279, 14280, 14281, 14282, 14283, 14284, 14285,14286, 14287, or 14288. In some embodiments, the siRNA comprises one ormore of the internucleoside linkages and/or nucleoside modifications ofthe antisense strand of 14167, 14169, 14170, 14172, 14174, 14175, 14176,14177, 14179, 14181, 14182, 14183, 14188, 14190, 14204, 14205, 14207,14209, 14210, 14212, 14213, 14215, 14223, 14230, 14234, 14235, 14236,14237, 14238, 14240, 14242, 14247, 14248, 14249, 14250, 14251, 14252,14254, 14257, 14259, 14264, 14269, 14270, 14271, 14275, 14278, 14279,14280, 14281, 14282, 14283, 14284, 14285, 14286, 14287, or 14288. Insome embodiments, the siRNA comprises the internucleoside linkagesand/or nucleoside modifications of the antisense strand of 14167, 14169,14170, 14172, 14174, 14175, 14176, 14177, 14179, 14181, 14182, 14183,14188, 14190, 14204, 14205, 14207, 14209, 14210, 14212, 14213, 14215,14223, 14230, 14234, 14235, 14236, 14237, 14238, 14240, 14242, 14247,14248, 14249, 14250, 14251, 14252, 14254, 14257, 14259, 14264, 14269,14270, 14271, 14275, 14278, 14279, 14280, 14281, 14282, 14283, 14284,14285, 14286, 14287, or 14288. In some embodiments, the siRNA isunmodified.

The siRNA may comprise an unmodified version of a sense strand sequenceof an siRNA that reduced an ANGPTL mRNA measurement by 10% or more,relative to a control, in Table 5 or Table 6. In some embodiments, thesiRNA comprises the sense strand sequence of any one of SEQ ID NOS: 32,33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484,509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134,1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285,1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702,1840, or 1842, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA comprises the sense strand sequence of any one of SEQ ID NOS:32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334,484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133,1134, 1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249,1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611,1702, 1840, or 1842, or a nucleic acid sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA comprises the sense strand sequence of any one of SEQ ID NOS:32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334,484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133,1134, 1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249,1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611,1702, 1840, or 1842. The siRNA may include the sense strand sequence ofany one of SEQ ID NOS: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292,321, 323, 326, 332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640,759, 834, 876, 1001, 1133, 1134, 1137, 1149, 1151, 1154, 1157, 1165,1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564,1580, 1581, 1589, 1597, 1611, 1702, 1840, or 1842, and one or moreinternucleoside linkages and/or one or more nucleoside modifications.The siRNA may include the sense strand sequence of any one of SEQ IDNOS: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332,334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001,1133, 1134, 1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248,1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597,1611, 1702, 1840, or 1842, and a modification pattern described herein(e.g. modification pattern 1S, 2S, 3S, 4S, 5S, or 6S).

The siRNA may comprise an unmodified version of an antisense strandsequence of an siRNA that reduced an ANGPTL mRNA measurement by 10% ormore, relative to a control, in Table 5 or Table 6. In some embodiments,the siRNA comprises the antisense strand sequence of any one of SEQ IDNOS: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175,2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491,2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011,3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344,3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696, or a nucleicacid sequence thereof having 3 or 4 nucleoside substitutions, additions,or deletions. In some embodiments, the siRNA comprises the antisensestrand sequence of any one of SEQ ID NOS: 1886, 1887, 1889, 1890, 1975,2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363,2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987,2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103,3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465,3556, 3694, or 3696, ora nucleic acid sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA comprises the antisense strand sequence of any one of SEQ IDNOS: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175,2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491,2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011,3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344,3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696. The siRNA mayinclude the antisense strand sequence of any one of SEQ ID NOS: 1886,1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180,2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613,2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020,3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434,3435, 3443, 3451, 3465, 3556, 3694, or 3696, and one or moreinternucleoside linkages and/or one or more nucleoside modifications.The siRNA may include the antisense strand sequence of any one of SEQ IDNOS: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175,2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491,2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011,3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344,3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696, and amodification pattern described herein (e.g. modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS).

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA in Table 7, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA in Table 7, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA in Table7. In some embodiments, the siRNA comprises one or more of theinternucleoside linkages and/or nucleoside modifications of the siRNA inTable 7. In some embodiments, the siRNA comprises the internucleosidelinkages and/or nucleoside modifications of the siRNA in Table 7. Insome embodiments, the siRNA is unmodified.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA in Table 8, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA in Table 8, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA in Table8. In some embodiments, the siRNA comprises one or more of theinternucleoside linkages and/or nucleoside modifications of the siRNA inTable 8. In some embodiments, the siRNA comprises the internucleosidelinkages and/or nucleoside modifications of the siRNA in Table 8. Insome embodiments, the siRNA is unmodified.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA in Table 10, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA in Table 10, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA in Table10. In some embodiments, the siRNA comprises one or more of theinternucleoside linkages and/or nucleoside modifications of the siRNA inTable 10. In some embodiments, the siRNA comprises the internucleosidelinkages and/or nucleoside modifications of the siRNA in Table 10. Insome embodiments, the siRNA is unmodified.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA in Table 15, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA in Table 15, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA in Table15. In some embodiments, the siRNA comprises one or more of theinternucleoside linkages and/or nucleoside modifications of the siRNA inTable 15. In some embodiments, the siRNA comprises the internucleosidelinkages and/or nucleoside modifications of the siRNA in Table 15. Insome embodiments, the siRNA is unmodified.

In some embodiments, the siRNA comprises the sense strand and/or theantisense strand sequence of an siRNA in Table 16, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA comprises the sense strandand/or the antisense strand sequence of an siRNA in Table 16, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA comprises thesense strand and/or the antisense strand sequence of an siRNA in Table16. In some embodiments, the siRNA comprises one or more of theinternucleoside linkages and/or nucleoside modifications of the siRNA inTable 16. In some embodiments, the siRNA comprises the internucleosidelinkages and/or nucleoside modifications of the siRNA in Table 16. Insome embodiments, the siRNA is unmodified.

In some embodiments, the sense strand comprises a nucleoside sequence atleast 85% identical to any one of SEQ ID NOS: 13970-13973. In someembodiments, the sense strand comprises the nucleoside sequence of anyone of SEQ ID NOS: 13970-13973, or a sense strand sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises the nucleoside sequence of anyone of SEQ ID NOS: 13970-13973. The siRNA may include the sense strandsequence of any one of SEQ ID NOS: 13970-13973, and one or moreinternucleoside linkages and/or one or more nucleoside modifications.The siRNA may include the sense strand sequence of any one of SEQ IDNOS: 13970-13973, and a modification pattern described herein (e.g.modification pattern 1S, 2S, 3S, 4S, 5S, or 6S). The sense strand mayinclude an overhang (e.g. a 2 nucleotide overhang such as 2 uracilnucleotides).

In some embodiments, the antisense strand comprises a nucleosidesequence at least 85% identical to any one of SEQ ID NOS: 13978-13981.In some embodiments, the antisense strand comprises the nucleosidesequence of any one of SEQ ID NOS: 13978-13981, or an antisense strandsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions. In some embodiments, the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOS: 13978-13981. The siRNA mayinclude the sense strand sequence of any one of SEQ ID NOS: 13978-13981,and one or more internucleoside linkages and/or one or more nucleosidemodifications. The siRNA may include the sense strand sequence of anyone of SEQ ID NOS: 13978-13981, and a modification pattern describedherein (e.g. modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS,8AS, or 9AS). The antisense strand may include an overhang (e.g. a 2nucleotide overhang such as 2 uracil nucleotides).

In some embodiments, the sense strand comprises a nucleoside sequence atleast 85% identical to any one of SEQ ID NOS: 13974-13977. In someembodiments, the sense strand comprises the nucleoside sequence of anyone of SEQ ID NOS: 13974-13977, or a sense strand sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises the nucleoside sequence of anyone of SEQ ID NOS: 13974-13977. The siRNA may include the sense strandsequence of any one of SEQ ID NOS: 13974-13977, and one or moreinternucleoside linkages and/or one or more nucleoside modifications.The siRNA may include the sense strand sequence of any one of SEQ IDNOS: 13974-13977, and a modification pattern described herein (e.g.modification pattern 1S, 2S, 3S, 4S, 5S, or 6S). The sense strand mayinclude an overhang.

In some embodiments, the antisense strand comprises a nucleosidesequence at least 85% identical to any one of SEQ ID NOS: 13982-13985.In some embodiments, the antisense strand comprises the nucleosidesequence of any one of SEQ ID NOS: 13982-13985, or an antisense strandsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions. In some embodiments, the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOS: 13982-13985. The siRNA mayinclude the sense strand sequence of any one of SEQ ID NOS: 13982-13985,and one or more internucleoside linkages and/or one or more nucleosidemodifications. The siRNA may include the sense strand sequence of anyone of SEQ ID NOS: 13982-13985, and a modification pattern describedherein (e.g. modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS,8AS, or 9AS). The antisense strand may include an overhang.

In some embodiments, the sense strand and/or antisense strand comprisesa nucleoside sequence at least 85% identical to the sense strand and/orantisense strand of any one of EDT01062 to ETD01065, EDT01062.1 toETD01065.1, EDT01062.2 to ETD01065.2, EDT01062.3 to ETD01065.3,EDT01062.4 to ETD01065.4, EDT01062.5 to ETD01065.5, EDT01062.6 toETD01065.6, EDT01062.7 to ETD01065.7, or EDT01062.8 to ETD01065.8. Insome embodiments, the sense strand and/or antisense strand comprises thesense strand and/or antisense strand of any one of EDT01062 to ETD01065,EDT01062.1 to ETD01065.1, EDT01062.2 to ETD01065.2, EDT01062.3 toETD01065.3, EDT01062.4 to ETD01065.4, EDT01062.5 to ETD01065.5,EDT01062.6 to ETD01065.6, EDT01062.7 to ETD01065.7, or EDT01062.8 toETD01065.8, or a sense strand and/or antisense strand sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand and/or antisense strand comprises thesense strand and/or antisense strand of any one of EDT01062 to ETD01065,EDT01062.1 to ETD01065.1, EDT01062.2 to ETD01065.2, EDT01062.3 toETD01065.3, EDT01062.4 to ETD01065.4, EDT01062.5 to ETD01065.5,EDT01062.6 to ETD01065.6, EDT01062.7 to ETD01065.7, or EDT01062.8 toETD01065.8. The sense strand and/or antisense strand may comprise aGalNAc ligand. The sense strand and/or antisense strand may exclude anyGalNAc ligand.

The sense strand may comprise the nucleoside sequence of SEQ ID NO:13973, or a derivative thereof. In some embodiments, the sense strandcomprises a nucleoside sequence at least 85% identical to SEQ ID NO:13973. The sense strand comprising the nucleoside sequence of SEQ ID NO:13973, or derivative thereof, may include the sense strand comprising anucleoside sequence at least 85% identical to SEQ ID NO: 13973. In someembodiments, the sense strand comprises the nucleoside sequence of SEQID NO: 13973, or a sense strand sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. The sense strandcomprising the nucleoside sequence of SEQ ID NO: 13973 derivative mayinclude the sense strand comprising a nucleoside sequence having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the sense strand comprises the nucleoside sequence of SEQ ID NO: 13973.The sense strand sequence may consist of the nucleotide sequence of SEQID NO: 13973. The sense strand comprising the nucleoside sequence of SEQID NO: 13973, or derivative thereof, may include a GalNAc ligand (e.g.attached to a 3′ or 5′ end). The sense strand comprising the nucleosidesequence of SEQ ID NO: 13973, or derivative thereof, may include a 2nucleotide overhang. The sense strand comprising the nucleoside sequenceof SEQ ID NO: 13973, or derivative thereof, may include modificationpattern 1S. The sense strand comprising the nucleoside sequence of SEQID NO: 13973, or derivative thereof, may include modification pattern2S. The sense strand comprising the nucleoside sequence of SEQ ID NO:13973, or derivative thereof, may include modification pattern 3S. Thesense strand comprising the nucleoside sequence of SEQ ID NO: 13973, orderivative thereof, may include modification pattern 4S. The sensestrand comprising the nucleoside sequence of SEQ ID NO: 13973, orderivative thereof, may include modification pattern 5S. The sensestrand comprising the nucleoside sequence of SEQ ID NO: 13973, orderivative thereof, may include modification pattern 6S.

The sense strand may comprise the nucleoside sequence of SEQ ID NO:13977, or a derivative thereof. In some embodiments, the sense strandcomprises a nucleoside sequence at least 85% identical to SEQ ID NO:13977. The sense strand comprising the nucleoside sequence of SEQ ID NO:13977, or derivative thereof, may include the sense strand comprising anucleoside sequence at least 85% identical to SEQ ID NO: 13977. In someembodiments, the sense strand comprises the nucleoside sequence of SEQID NO: 13977, or a sense strand sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions. The sense strandcomprising the nucleoside sequence of SEQ ID NO: 13977 derivative mayinclude the sense strand comprising a nucleoside sequence having 1 or 2nucleoside substitutions, additions, or deletions. In some embodiments,the sense strand comprises the nucleoside sequence of SEQ ID NO: 13977.The sense strand sequence may consist of the nucleotide sequence of SEQID NO: 13977. The sense strand comprising the nucleoside sequence of SEQID NO: 13977, or derivative thereof, may include a GalNAc ligand (e.g.attached to a 3′ or 5′ end). The sense strand comprising the nucleosidesequence of SEQ ID NO: 13977, or derivative thereof, may include a 2nucleotide overhang. The sense strand comprising the nucleoside sequenceof SEQ ID NO: 13977, or derivative thereof, may include modificationpattern 1S. The sense strand comprising the nucleoside sequence of SEQID NO: 13977, or derivative thereof, may include modification pattern2S. The sense strand comprising the nucleoside sequence of SEQ ID NO:13977, or derivative thereof, may include modification pattern 3S. Thesense strand comprising the nucleoside sequence of SEQ ID NO: 13977, orderivative thereof, may include modification pattern 4S. The sensestrand comprising the nucleoside sequence of SEQ ID NO: 13977, orderivative thereof, may include modification pattern 5S. The sensestrand comprising the nucleoside sequence of SEQ ID NO: 13977, orderivative thereof, may include modification pattern 6S.

The antisense strand may comprise the nucleoside sequence of SEQ ID NO:13981, or a derivative thereof. In some embodiments, the antisensestrand comprises a nucleoside sequence at least 85% identical to SEQ IDNO: 13981. The antisense strand comprising the nucleoside sequence ofSEQ ID NO: 13981, or derivative thereof, may include the antisensestrand comprising a nucleoside sequence at least 85% identical to SEQ IDNO: 13981. In some embodiments, the antisense strand comprises thenucleoside sequence of SEQ ID NO: 13981, or an antisense strand sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions.The antisense strand comprising the nucleoside sequence of SEQ ID NO:13981 derivative may include the antisense strand comprising anucleoside sequence having 1 or 2 nucleoside substitutions, additions,or deletions. In some embodiments, the antisense strand comprises thenucleoside sequence of SEQ ID NO: 13981. The antisense strand sequencemay consist of the nucleotide sequence of SEQ ID NO: 13981. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13981,or derivative thereof, may include a GalNAc ligand (e.g. attached to a3′ or 5′ end). The antisense strand comprising the nucleoside sequenceof SEQ ID NO: 13981, or derivative thereof, may include a 2 nucleotideoverhang. The antisense strand comprising the nucleoside sequence of SEQID NO: 13981, or derivative thereof, may include modification pattern1AS. The antisense strand comprising the nucleoside sequence of SEQ IDNO: 13981, or derivative thereof, may include modification pattern 2AS.The antisense strand comprising the nucleoside sequence of SEQ ID NO:13981, or derivative thereof, may include modification pattern 3AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13981,or derivative thereof, may include modification pattern 4AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13981,or derivative thereof, may include modification pattern 5AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13981,or derivative thereof, may include modification pattern 6AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13981,or derivative thereof, may include modification pattern 7AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13981,or derivative thereof, may include modification pattern 8AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13981,or derivative thereof, may include modification pattern 9AS.

The antisense strand may comprise the nucleoside sequence of SEQ ID NO:13985, or a derivative thereof. In some embodiments, the antisensestrand comprises a nucleoside sequence at least 85% identical to SEQ IDNO: 13985. The antisense strand comprising the nucleoside sequence ofSEQ ID NO: 13985, or derivative thereof, may include the antisensestrand comprising a nucleoside sequence at least 85% identical to SEQ IDNO: 13985. In some embodiments, the antisense strand comprises thenucleoside sequence of SEQ ID NO: 13985, or an antisense strand sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions.The antisense strand comprising the nucleoside sequence of SEQ ID NO:13985 derivative may include the antisense strand comprising anucleoside sequence having 1 or 2 nucleoside substitutions, additions,or deletions. In some embodiments, the antisense strand comprises thenucleoside sequence of SEQ ID NO: 13985. The antisense strand sequencemay consist of the nucleotide sequence of SEQ ID NO: 13985. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13985,or derivative thereof, may include a GalNAc ligand (e.g. attached to a3′ or 5′ end). The antisense strand comprising the nucleoside sequenceof SEQ ID NO: 13985, or derivative thereof, may include a 2 nucleotideoverhang. The antisense strand comprising the nucleoside sequence of SEQID NO: 13985, or derivative thereof, may include modification pattern1AS. The antisense strand comprising the nucleoside sequence of SEQ IDNO: 13985, or derivative thereof, may include modification pattern 2AS.The antisense strand comprising the nucleoside sequence of SEQ ID NO:13985, or derivative thereof, may include modification pattern 3AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13985,or derivative thereof, may include modification pattern 4AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13985,or derivative thereof, may include modification pattern 5AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13985,or derivative thereof, may include modification pattern 6AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13985,or derivative thereof, may include modification pattern 7AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13985,or derivative thereof, may include modification pattern 8AS. Theantisense strand comprising the nucleoside sequence of SEQ ID NO: 13985,or derivative thereof, may include modification pattern 9AS.

In some embodiments, the sense strand comprises a nucleoside sequence atleast 85% identical to any one of SEQ ID NOS: 14006-14011. In someembodiments, the sense strand comprises the nucleoside sequence of anyone of SEQ ID NOS: 14006-14011, or a sense strand sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the sense strand comprises the nucleoside sequence of anyone of SEQ ID NOS: 14006-14011. The sense strand may comprise a GalNAcligand. In some embodiments, the antisense strand comprises a nucleosidesequence at least 85% identical to any one of SEQ ID NOS: 14158-14166.In some embodiments, the antisense strand comprises the nucleosidesequence of any one of SEQ ID NOS: 14158-14166, or an antisense strandsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions. In some embodiments, the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOS: 14158-14166. The antisensestrand may comprise a GalNAc ligand.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 13970, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 13970, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 13970. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 13978, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 13978, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 13978. In some embodiments, the antisense strand comprisesone or more internucleoside linkages and/or nucleoside modifications.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 13971, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 13971, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 13971. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 13979, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 13979, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 13979. In some embodiments, the antisense strand comprisesone or more intemucleoside linkages and/or nucleoside modifications.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 13972, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 13972, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 13972. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 13980, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 13980, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 13980. In some embodiments, the antisense strand comprisesone or more intemucleoside linkages and/or nucleoside modifications.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 13973, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 13973, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 13973. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 13981, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 13981, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 13981. In some embodiments, the antisense strand comprisesone or more internucleoside linkages and/or nucleoside modifications.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 1285, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 1285, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 1285. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 3139, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 3139, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 3139. In some embodiments, the antisense strand comprises oneor more internucleoside linkages and/or nucleoside modifications.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 1580, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 1580, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 1580. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 3434, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 3434, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 3434. In some embodiments, the antisense strand comprises oneor more internucleoside linkages and/or nucleoside modifications.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 13974, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 13974, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 13974. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 13982, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 13982, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 13982. In some embodiments, the antisense strand comprisesone or more internucleoside linkages and/or nucleoside modifications.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 13975, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 13975, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 13975. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 13983, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 13983, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 13983. In some embodiments, the antisense strand comprisesone or more internucleoside linkages and/or nucleoside modifications.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 13976, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 13976, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 13976. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 13984, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 13984, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 13984. In some embodiments, the antisense strand comprisesone or more internucleoside linkages and/or nucleoside modifications.

In some embodiments, the siRNA a sense strand comprising the sequence ofSEQ ID NO: 13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments,the siRNA a sense strand comprising the sequence of SEQ ID NO: 13977, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the siRNA a sense strandcomprising the sequence of SEQ ID NO: 13977. In some embodiments, thesense strand comprises one or more internucleoside linkages and/ornucleoside modifications. In some embodiments, the siRNA an antisensestrand comprising the sequence of SEQ ID NO: 13985, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions. In some embodiments, the siRNA an antisense strand comprisingthe sequence of SEQ ID NO: 13985, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the siRNA an antisense strand comprising the sequence ofSEQ ID NO: 13985. In some embodiments, the antisense strand comprisesone or more internucleoside linkages and/or nucleoside modifications.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand,wherein the antisense strand comprises a seed region that is notidentical to a seed region of a human miRNA. In some embodiments, thecomposition comprises an oligonucleotide that inhibits the expression ofANGPTL4, wherein the oligonucleotide comprises an siRNA comprising asense strand and an antisense strand, wherein the sense strand comprisesa seed region that is not identical to a seed region of a human miRNA.In some embodiments, the siRNA is cross-reactive with a non-humanprimate (NHP) ANGPTL4 mRNA. For example, the antisense strand may bindto, or be complementary with, the NHP ANGPTL4 mRNA.

B. ASOs

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an antisense oligonucleotide (ASO). In some embodiments, theASO is 12-30 nucleosides in length. In some embodiments, the ASO is14-30 nucleosides in length. In some embodiments, the ASO is at leastabout 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 nucleosides in length, or a range defined by anyof the two aforementioned numbers. In some embodiments, the ASO is 15-25nucleosides in length. In some embodiments, the ASO is 20 nucleosides inlength.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an antisense oligonucleotide (ASO) about 12-30 nucleosides inlength and comprising a nucleoside sequence complementary to about 12-30contiguous nucleosides of a full-length human ANGPTL4 mRNA sequence suchas SEQ ID NO: 13935; wherein (i) the oligonucleotide comprises amodification comprising a modified nucleoside and/or a modifiedintemucleoside linkage, and/or (ii) the composition comprises apharmaceutically acceptable carrier.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an ASO about 12-30 nucleosides in length and comprising anucleoside sequence complementary to about 12-30 contiguous nucleosidesof a full-length human ANGPTL4 mRNA sequence such as SEQ ID NO: 13936;wherein (i) the oligonucleotide comprises a modification comprising amodified nucleoside and/or a modified internucleoside linkage, and/or(ii) the composition comprises a pharmaceutically acceptable carrier.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an ASO that comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 3709-13934. In someembodiments, the ASO comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 3709-13934, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the ASO comprises anucleoside sequence comprising or consisting of the sequence of any oneof SEQ ID NOs: 3709-13934, or a nucleic acid sequence thereof having 3or 4 nucleoside substitutions, additions, or deletions.

C. Modification Patterns

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises a modification comprising a modified nucleoside and/or amodified internucleoside linkage, and/or (ii) the composition comprisesa pharmaceutically acceptable carrier. In some embodiments, theoligonucleotide comprises a modification comprising a modifiednucleoside and/or a modified internucleoside linkage. In someembodiments, the oligonucleotide comprises a modified internucleosidelinkage. In some embodiments, the modified internucleoside linkagecomprises alkylphosphonate, phosphorothioate, methylphosphonate,phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate,carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or acombination thereof. In some embodiments, the modified internucleosidelinkage comprises one or more phosphorothioate linkages. Benefits of themodified internucleoside linkage may include decreased toxicity orimproved pharmacokinetics.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises a modified internucleoside linkage, wherein theoligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a rangeof modified internucleoside linkages defined by any two of theaforementioned numbers. In some embodiments, the oligonucleotidecomprises no more than 18 modified internucleoside linkages. In someembodiments, the oligonucleotide comprises no more than 20 modifiedinternucleoside linkages. In some embodiments, the oligonucleotidecomprises 2 or more modified internucleoside linkages, 3 or moremodified internucleoside linkages, 4 or more modified internucleosidelinkages, 5 or more modified internucleoside linkages, 6 or moremodified internucleoside linkages, 7 or more modified internucleosidelinkages, 8 or more modified internucleoside linkages, 9 or moremodified internucleoside linkages, 10 or more modified internucleosidelinkages, 11 or more modified internucleoside linkages, 12 or moremodified internucleoside linkages, 13 or more modified internucleosidelinkages, 14 or more modified internucleoside linkages, 15 or moremodified internucleoside linkages, 16 or more modified internucleosidelinkages, 17 or more modified internucleoside linkages, 18 or moremodified internucleoside linkages, 19 or more modified internucleosidelinkages, or 20 or more modified internucleoside linkages.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises the modified nucleoside. In some embodiments, the modifiednucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid(HLA), cyclohexene nucleic acid (CeNA), 2′-methoxyethyl, 2′-O-alkyl,2′-O-allyl, 2′-fluoro, or 2′-deoxy, or a combination thereof. In someembodiments, the modified nucleoside comprises a LNA. In someembodiments, the modified nucleoside comprises a 2′,4′ constrained ethylnucleic acid. In some embodiments, the modified nucleoside comprisesHLA. In some embodiments, the modified nucleoside comprises CeNA. Insome embodiments, the modified nucleoside comprises a 2′-methoxyethylgroup. In some embodiments, the modified nucleoside comprises a2′-O-alkyl group. In some embodiments, the modified nucleoside comprisesa 2′-O-allyl group. In some embodiments, the modified nucleosidecomprises a 2′-fluoro group. In some embodiments, the modifiednucleoside comprises a 2′-deoxy group. In some embodiments, the modifiednucleoside comprises a 2′-O-methyl nucleoside, 2′-deoxyfluoronucleoside, 2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl(2′-O-AP) nucleoside, or 2′-ara-F, or a combination thereof. In someembodiments, the modified nucleoside comprises a 2′-O-methyl nucleoside.In some embodiments, the modified nucleoside comprises a 2′-deoxyfluoronucleoside. In some embodiments, the modified nucleoside comprises a2′-O-NMA nucleoside. In some embodiments, the modified nucleosidecomprises a 2′-O-DMAEOE nucleoside. In some embodiments, the modifiednucleoside comprises a 2′-O-aminopropyl (2′-O-AP) nucleoside. In someembodiments, the modified nucleoside comprises 2′-ara-F. In someembodiments, the modified nucleoside comprises one or more 2′fluoromodified nucleosides. In some embodiments, the modified nucleosidecomprises a 2′ O-alkyl modified nucleoside. Benefits of the modifiednucleoside may include decreased toxicity or improved pharmacokinetics.

In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modifiednucleosides, or a range of nucleosides defined by any two of theaforementioned numbers. In some embodiments, the oligonucleotidecomprises no more than 19 modified nucleosides. In some embodiments, theoligonucleotide comprises no more than 21 modified nucleosides. In someembodiments, the oligonucleotide comprises 2 or more modifiednucleosides, 3 or more modified nucleosides, 4 or more modifiednucleosides, 5 or more modified nucleosides, 6 or more modifiednucleosides, 7 or more modified nucleosides, 8 or more modifiednucleosides, 9 or more modified nucleosides, 10 or more modifiednucleosides, 11 or more modified nucleosides, 12 or more modifiednucleosides, 13 or more modified nucleosides, 14 or more modifiednucleosides, 15 or more modified nucleosides, 16 or more modifiednucleosides, 17 or more modified nucleosides, 18 or more modifiednucleosides, 19 or more modified nucleosides, 20 or more modifiednucleosides, or 21 or more modified nucleosides.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises a lipid attached at a 3′ or 5′ terminus of theoligonucleotide. In some embodiments, the lipid comprises cholesterol,myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl,docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or acombination thereof.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an N-acetylgalactosamine (GalNAc) ligand for hepatocytetargeting. A “GalNAc ligand” may be refer to a ligand for anasialoglycoprotein receptor (e.g. on a hepatocyte) that comprises one ormore GalNAc moieties. The GalNAc ligand may bind an asialoglycoproteinreceptor (e.g. on a hepatocyte). The GalNAc ligand may comprise one ormore GalNAc moieties. An example of a GalNAc moiety includes GalNAcattached to a linker. The GalNAc ligand may comprise 3 GalNAc moieties.The GalNAc ligand may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or moreGalNAc moieties.

The GalNAc ligand may be conjugated to the oligonucleotide. The GalNAcligand may be conjugated to a 5′ end of the oligonucleotide. The GalNAcligand may be conjugated to a 3′ end of the oligonucleotide. A firstGalNAc ligand may be conjugated to a 5′ end of the oligonucleotide, anda second GalNAc ligand may be conjugated to 3′ end of theoligonucleotide. The GalNAc ligand may be conjugated to a 3′ or 5′ endof an ASO. The GalNAc ligand may be conjugated to a 3′ or 5′ end of asense strand of an siRNA. The GalNAc ligand may be conjugated to a 3′end of a sense strand of an siRNA. The GalNAc ligand may be conjugatedto a 5′ end of a sense strand of an siRNA. The GalNAc ligand may beconjugated to a 3′ or 5′ end of an antisense strand of an siRNA. TheGalNAc ligand may be conjugated to a 3′ end of an antisense strand of ansiRNA. The GalNAc ligand may be conjugated to a 5′ end of an antisensestrand of an siRNA. A first GalNAc ligand may be conjugated to a sensestrand of an siRNA, and a second GalNAc ligand may be conjugated to anantisense strand of the siRNA.

1. siRNA Modification Patterns

In some embodiments, the sense strand comprises 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, or 29 modified internucleoside linkages, or a range of modifiedinternucleoside linkages defined by any two of the aforementionedintegers. In some embodiments, the sense strand comprises 1-11 modifiedinternucleoside linkages. In some embodiments, the sense strandcomprises 2-6 modified internucleoside linkages. In some embodiments,the sense strand comprises 5 modified internucleoside linkages. In someembodiments, the sense strand comprises 4 modified internucleosidelinkages.

In some embodiments, the antisense strand comprises 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, or 29 modified internucleoside linkages, or a range ofmodified internucleoside linkages defined by any two of theaforementioned integers. In some embodiments, the antisense strandcomprises 1-11 modified internucleoside linkages. In some embodiments,the antisense strand comprises 2-6 modified internucleoside linkages. Insome embodiments, the antisense strand comprises 5 modifiedinternucleoside linkages. In some embodiments, the antisense strandcomprises 4 modified internucleoside linkages.

In some embodiments, the sense strand comprises 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29 or 30 modified nucleosides, or a range of modifiednucleosides defined by any two of the aforementioned integers. In someembodiments, the sense strand comprises 12-19 modified nucleosides. Insome embodiments, the sense strand comprises 12-21 modified nucleosides.In some embodiments, the sense strand comprises 19 modified nucleosides.In some embodiments, the sense strand comprises 21 modified nucleosides.

In some embodiments, the antisense strand comprises 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29 or 30 modified nucleosides, or a range of modifiednucleosides defined by any two of the aforementioned integers. In someembodiments, the antisense strand comprises 12-19 modified nucleosides.In some embodiments, the antisense strand comprises 12-21 modifiednucleosides. In some embodiments, the antisense strand comprises 19modified nucleosides. In some embodiments, the antisense strandcomprises 21 modified nucleosides.

In some embodiments, the sense strand or the antisense strand furthercomprises at least 2 additional nucleosides attached to a 3′ terminus ofthe sense strand or the antisense strand. In some embodiments, the sensestrand or the antisense strand comprises 2 additional nucleosidesattached to a 3′ terminus of the sense strand or the antisense strand.As part of the sense strand, the additional nucleosides may or may notbe complementary to an ANGPTL4 mRNA. The additional nucleosides of theantisense strand may include a uracil. The 2 additional nucleosides ofthe antisense strand may both include uracil.

In some embodiments, the sense strand or the sense strand furthercomprises at least 2 additional nucleosides attached to a 3′ terminus ofthe sense strand or the sense strand. In some embodiments, the sensestrand or the sense strand comprises 2 additional nucleosides attachedto a 3′ terminus of the sense strand or the sense strand. The additionalnucleosides of the sense strand may include a uracil. The 2 additionalnucleosides of the sense strand may both include uracil.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein thesense strand comprises modification pattern 1S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13954), wherein“Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the sense strand comprises modification pattern 2S:5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13955), wherein “Nf” isa 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the sense strand comprises modification pattern 3S:5′-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13956), wherein “Nf” is a2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage. In some embodiments, the sensestrand comprises modification pattern 4S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3′ (SEQ ID NO: 13957), wherein“Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, “s” is a phosphorothioate linkage, and N comprises one ormore nucleosides. In some embodiments, the sense strand comprisesmodification pattern 5S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3′ (SEQ IDNO: 13958), wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′O-methyl modified nucleoside, “s” is a phosphorothioate linkage, and Ncomprises one or more nucleosides. In some embodiments, the sense strandcomprises modification pattern 6S:5′-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13959), wherein“Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, “s” is a phosphorothioate linkage, and N comprises one ormore nucleosides. Any one of modification patterns 1S-6S may include aGalNAc ligand attached to the 3′ end. Any one of modification patterns1S-6S may include a GalNAc ligand attached to the 5′ end.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises modification pattern 1AS:5′-nsNfsnNfnNfnNfnNfrmnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13960), wherein “Nf”is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the antisense strand comprises modification pattern 2AS:5′-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13961), wherein “Nf”is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the antisense strand comprises modification pattern 3AS:5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13962), wherein “Nf” isa 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the antisense strand comprises modification pattern 4AS:5′-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13963), wherein “Nf” isa 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the antisense strand comprises modification pattern 5AS:5′-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13964), wherein “Nf” isa 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the antisense strand comprises modification pattern 6AS:5′-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13965), wherein“Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the antisense strand comprises modification pattern 7AS:5′-nsNfsnNfnNfnNfNfnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13966), wherein “Nf”is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the antisense strand comprises modification pattern 8AS:5′-nsNfsnnnnnnnnnnnNfnrmnnsnsn-3′ (SEQ ID NO: 13967), wherein “Nf” is a2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage. In some embodiments, theantisense strand comprises modification pattern 9AS:5′-nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13968), wherein “Nf” isa 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage. Any one ofmodification patterns 1AS-9AS may include a GalNAc ligand attached tothe 3′ end. Any one of modification patterns 1AS-9AS may include aGalNAc ligand attached to the 5′ end.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein thesense strand comprises modification pattern 1S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand comprises modificationpattern 2S and the antisense strand comprises modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, thesense strand comprises modification pattern 3S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand comprises modificationpattern 4S and the antisense strand comprises modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, thesense strand comprises modification pattern 5S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand comprises modificationpattern 6S and the antisense strand comprises modification pattern 1AS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, thesense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS,6AS, 7AS, 8AS, or 9AS. In some embodiments, the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,or 9AS. In some embodiments, the sense strand or the antisense strandcomprises modification pattern ASO1.

Any combination of sense and antisense modification patterns may beused. In some embodiments, the sense strand comprises modificationpattern 15, and the antisense strand comprises modification pattern 1AS.In some embodiments, the sense strand comprises modification pattern 2S,and the antisense strand comprises modification pattern 2AS. In someembodiments, the sense strand comprises modification pattern 2S, and theantisense strand comprises modification pattern 3AS. In someembodiments, the sense strand comprises modification pattern 3S, and theantisense strand comprises modification pattern 1AS. In someembodiments, the sense strand comprises modification pattern 3S, and theantisense strand comprises modification pattern 4AS. In someembodiments, the sense strand comprises modification pattern 3S, and theantisense strand comprises modification pattern 5AS. In someembodiments, the sense strand comprises modification pattern 3S, and theantisense strand comprises modification pattern 6AS. In someembodiments, the sense strand comprises modification pattern 3S, and theantisense strand comprises modification pattern 7AS. In someembodiments, the sense strand comprises modification pattern 3S, and theantisense strand comprises modification pattern 8AS. In someembodiments, the sense strand comprises modification pattern 6S, and theantisense strand comprises modification pattern 1AS. In someembodiments, the sense strand comprises modification pattern 6S, and theantisense strand comprises modification pattern 4AS. In someembodiments, the sense strand comprises modification pattern 6S, and theantisense strand comprises modification pattern 5AS. In someembodiments, the sense strand comprises modification pattern 6S, and theantisense strand comprises modification pattern 6AS. In someembodiments, the sense strand comprises modification pattern 6S, and theantisense strand comprises modification pattern 7AS. In someembodiments, the sense strand comprises modification pattern 6S, and theantisense strand comprises modification pattern 8AS.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein thesense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, andmodification pattern 15. In some embodiments, the sense strand comprisesa nucleoside sequence comprising or consisting of the sequence of anyone of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions,and modification pattern 1S. In some embodiments, the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions, and modification pattern 1S.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein thesense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, andmodification pattern 2S. In some embodiments, the sense strand comprisesa nucleoside sequence comprising or consisting of the sequence of anyone of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions,and modification pattern 2S. In some embodiments, the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions, and modification pattern 2S.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein thesense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, andmodification pattern 3S. In some embodiments, the sense strand comprisesa nucleoside sequence comprising or consisting of the sequence of anyone of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions,and modification pattern 3S. In some embodiments, the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions, and modification pattern 3S.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein thesense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, andmodification pattern 4S. In some embodiments, the sense strand comprisesa nucleoside sequence comprising or consisting of the sequence of anyone of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions,and modification pattern 4S. In some embodiments, the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions, and modification pattern 4S.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein thesense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, andmodification pattern 5S. In some embodiments, the sense strand comprisesa nucleoside sequence comprising or consisting of the sequence of anyone of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions,and modification pattern 5S. In some embodiments, the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions, and modification pattern 5S.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein thesense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, andmodification pattern 6S. In some embodiments, the sense strand comprisesa nucleoside sequence comprising or consisting of the sequence of anyone of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions,and modification pattern 6S. In some embodiments, the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acidsequence thereof having 3 or 4 nucleoside substitutions, additions, ordeletions, and modification pattern 6S.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 1AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 1AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions, and modificationpattern 1AS.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 2AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 2AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions, and modificationpattern 2AS.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 3AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 3AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions, and modificationpattern 3AS.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 4AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 4AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions, and modificationpattern 4AS.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 5AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 5AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions, and modificationpattern 5AS.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 6AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 6AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions, and modificationpattern 6AS.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 7AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 7AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions, and modificationpattern 7AS.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 8AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 8AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions, and modificationpattern 8AS.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4 wherein the oligonucleotide comprisesan siRNA comprising a sense strand and an antisense strand, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, and modification pattern 9AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 9AS. Insome embodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions, and modificationpattern 9AS.

In some embodiments, the sense strand comprises a nucleoside sequencecomprising or consisting the sequence of any one of SEQ ID NOs: 1-1854or 13970-13977, an overhang (such as a 2 base 3′ overhang), andmodification pattern 1S. In some embodiments, the sense strand comprisesa nucleoside sequence comprising or consisting the sequence of any oneof SEQ ID NOs: 1-1854 or 13970-13977, an overhang (such as a 2 base 3′overhang), and modification pattern 2S. In some embodiments, the sensestrand comprises a nucleoside sequence comprising or consisting thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, an overhang(such as a 2 base 3′ overhang), and modification pattern 3S. In someembodiments, the sense strand comprises a nucleoside sequence comprisingor consisting the sequence of any one of SEQ ID NOs: 1-1854 or13970-13977, an overhang (such as a 2 base 3′ overhang), andmodification pattern 4S. In some embodiments, the sense strand comprisesa nucleoside sequence comprising or consisting the sequence of any oneof SEQ ID NOs: 1-1854 or 13970-13977, an overhang (such as a 2 base 3′overhang), and modification pattern 5S. In some embodiments, the sensestrand comprises a nucleoside sequence comprising or consisting thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, an overhang(such as a 2 base 3′ overhang), and modification pattern 6S. In someembodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1855-3708 or 13978-13985, and an overhang (such as a 2 base 3′overhang), and modification pattern 1AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, and an overhang (such as a 2 base 3′ overhang), andmodification pattern 2AS. In some embodiments, the antisense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1855-3708 or 13978-13985, and an overhang(such as a 2 base 3′ overhang), and modification pattern 3AS. In someembodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1855-3708 or 13978-13985, and an overhang (such as a 2 base 3′overhang), and modification pattern 4AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, and an overhang (such as a 2 base 3′ overhang), andmodification pattern 5AS. In some embodiments, the antisense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1855-3708 or 13978-13985, and an overhang(such as a 2 base 3′ overhang), and modification pattern 6AS. In someembodiments, the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:1855-3708 or 13978-13985, and an overhang (such as a 2 base 3′overhang), and modification pattern 7AS. In some embodiments, theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, and an overhang (such as a 2 base 3′ overhang), andmodification pattern 8AS. In some embodiments, the antisense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1855-3708 or 13978-13985, and an overhang(such as a 2 base 3′ overhang), and modification pattern 9AS. In someembodiments, the overhang comprises one or more uracil nucleosides. Insome embodiments, the one or more uracil nucleosides of the overhang areconnected at the 3′ end to another nucleoside via a phosphorothioatelinkage. In some embodiments, the overhang comprises one uracilnucleoside. In some embodiments, the overhang comprises two uracilnucleoside.

Some embodiments include a composition comprising an oligonucleotidethat targets Angiopoietin like 4 (ANGPTL4) and when administered to acell decreases expression of ANGPTL4, wherein the oligonucleotidecomprises a small interfering RNA (siRNA) comprising a sense strand andan antisense strand, wherein the sense strand comprises anoligonucleotide sequence of SEQ ID NOs: 759, 1285, 1580, or 1840 inwhich at least one internucleoside linkage is modified and at least onebase is modified, or an oligonucleotide sequence comprising 1 or 2nucleoside, substitutions, additions, or deletions of SEQ ID NOs: 759,1285, 1580, or 1840 in which at least one internucleoside linkage ismodified and at least one base is modified, and wherein the antisensestrand comprises an oligonucleotide sequence of SEQ ID NOs: 2613, 3139,3434, or 3694 in which at least one internucleoside linkage is modifiedand at least one base is modified, or an oligonucleotide sequencecomprising 1 or 2 nucleoside, substitutions, additions, or deletions ofSEQ ID NOs: 2613, 3139, 3434, or 3694 in which at least oneinternucleoside linkage is modified and at least one base is modified.

Some embodiments include a composition comprising an oligonucleotidethat targets Angiopoietin like 4 (ANGPTL4) and when administered to acell decreases expression of ANGPTL4, wherein the oligonucleotidecomprises a small interfering RNA (siRNA) comprising a sense strand andan antisense strand, wherein the sense strand comprises anoligonucleotide sequence of any one of SEQ ID NOs: 13970-13973 in whichat least one intemucleoside linkage is modified and at least one base ismodified, or an oligonucleotide sequence comprising 1 or 2 nucleoside,substitutions, additions, or deletions of any one of SEQ ID NOs:13970-13973 in which at least one internucleoside linkage is modifiedand at least one base is modified, and wherein the antisense strandcomprises an oligonucleotide sequence of any one of SEQ ID NOs:13978-13981 in which at least one internucleoside linkage is modifiedand at least one base is modified, or an oligonucleotide sequencecomprising 1 or 2 nucleoside, substitutions, additions, or deletions ofany one of SEQ ID NOs: 13978-13981 in which at least one internucleosidelinkage is modified and at least one base is modified.

Some embodiments include a composition comprising an oligonucleotidethat targets Angiopoietin like 4 (ANGPTL4) and when administered to acell decreases expression of ANGPTL4, wherein the oligonucleotidecomprises a small interfering RNA (siRNA) comprising a sense strand andan antisense strand, wherein the sense strand comprises anoligonucleotide sequence of any one of SEQ ID NOs: 13974-13977 in whichat least one intemucleoside linkage is modified and at least one base ismodified, or an oligonucleotide sequence comprising 1 or 2 nucleoside,substitutions, additions, or deletions of any one of SEQ ID NOs:13974-13977 in which at least one internucleoside linkage is modifiedand at least one base is modified, and wherein the antisense strandcomprises an oligonucleotide sequence of any one of SEQ ID NOs:13982-13985 in which at least one internucleoside linkage is modifiedand at least one base is modified, or an oligonucleotide sequencecomprising 1 or 2 nucleoside, substitutions, additions, or deletions ofany one of SEQ ID NOs: 13982-13985 in which at least one internucleosidelinkage is modified and at least one base is modified.

Some embodiments include a composition comprising an oligonucleotidethat targets Angiopoietin like 4 (ANGPTL4) and when administered to acell decreases expression of ANGPTL4, wherein the oligonucleotidecomprises a small interfering RNA (siRNA) comprising a sense strand andan antisense strand, wherein the sense strand comprises anoligonucleotide sequence of any one of SEQ ID NOs: 13990-14005 in whichat least one internucleoside linkage is modified and at least one baseis modified, or an oligonucleotide sequence comprising 1 or 2nucleoside, substitutions, additions, or deletions of any one of SEQ IDNOs: 13990-14005 in which at least one internucleoside linkage ismodified and at least one base is modified, and wherein the antisensestrand comprises an oligonucleotide sequence of any one of SEQ ID NOs:14134-14157 in which at least one internucleoside linkage is modifiedand at least one base is modified, or an oligonucleotide sequencecomprising 1 or 2 nucleoside, substitutions, additions, or deletions ofany one of SEQ ID NOs: 14134-14157 in which at least one internucleosidelinkage is modified and at least one base is modified.

Some embodiments include a composition comprising an oligonucleotidethat targets Angiopoietin like 4 (ANGPTL4) and when administered to acell decreases expression of ANGPTL4, wherein the oligonucleotidecomprises a small interfering RNA (siRNA) comprising a sense strand andan antisense strand, wherein the sense strand comprises anoligonucleotide sequence of any one of SEQ ID NOs: 1-1854 in which atleast one internucleoside linkage is modified and at least one base ismodified, or an oligonucleotide sequence comprising 1 or 2 nucleoside,substitutions, additions, or deletions of any one of SEQ ID NOs: 1-1854in which at least one internucleoside linkage is modified and at leastone base is modified, and wherein the antisense strand comprises anoligonucleotide sequence of any one of SEQ ID NOs: 1855-3708 in which atleast one internucleoside linkage is modified and at least one base ismodified, or an oligonucleotide sequence comprising 1 or 2 nucleoside,substitutions, additions, or deletions of any one of SEQ ID NOs:1855-3708 in which at least one internucleoside linkage is modified andat least one base is modified.

2. ASO Modification Patterns

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an antisense oligonucleotide (ASO). In some embodiments, theASO comprises modification pattern ASO1:5′-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3′, wherein “dN” isany deoxynucleotide, “n” is a 2′O-methyl or 2′O-methoxyethyl-modifiednucleoside, and “s” is a phosphorothioate linkage. In some embodiments,the ASO comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 1AS, 2AS,3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the ASOcomprises DNA.

In some embodiments, the composition comprises an oligonucleotide thatinhibits the expression of ANGPTL4, wherein the oligonucleotidecomprises an antisense oligonucleotide (ASO). In some embodiments, theASO comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 3709-13934, and modification patternASO1. In some embodiments, the ASO comprises a nucleoside sequencecomprising or consisting of the sequence of any one of SEQ ID NOs:3709-13934, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern ASO1.In some embodiments, the ASO comprises a nucleoside sequence comprisingor consisting of the sequence of any one of SEQ ID NOs: 3709-13934, or anucleic acid sequence thereof having 3 or 4 nucleoside substitutions,additions, or deletions, and modification pattern ASO1.

ASO1 modification pattern ASO1 may include a GalNAc ligand attached tothe 3′ end. ASO1 modification pattern ASO1 may include a GalNAc ligandattached to the 5′ end.

D. Formulations

In some embodiments, the composition is a pharmaceutical composition. Insome embodiments, the composition is sterile. In some embodiments, thecomposition further comprises a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutically acceptable carrier compriseswater. In some embodiments, the pharmaceutically acceptable carriercomprises a buffer. In some embodiments, the pharmaceutically acceptablecarrier comprises a saline solution. In some embodiments, thepharmaceutically acceptable carrier comprises water, a buffer, or asaline solution. In some embodiments, the composition comprises aliposome. In some embodiments, the pharmaceutically acceptable carriercomprises liposomes, lipids, nanoparticles, proteins, protein-antibodycomplexes, peptides, cellulose, nanogel, or a combination thereof.

II. Methods and Uses

Disclosed herein, in some embodiments, are methods of administering acomposition described herein to a subject. Some embodiments relate touse a composition described herein, such as administering thecomposition to a subject.

Some embodiments relate to a method of treating a disorder in a subjectin need thereof. Some embodiments relate to use of a compositiondescribed herein in the method of treatment. Some embodiments includeadministering a composition described herein to a subject with thedisorder. In some embodiments, the administration treats the disorder inthe subject. In some embodiments, the composition treats the disorder inthe subject.

In some embodiments, the treatment comprises prevention, inhibition, orreversion of the disorder in the subject. Some embodiments relate to useof a composition described herein in the method of preventing,inhibiting, or reversing the disorder. Some embodiments relate to amethod of preventing, inhibiting, or reversing a disorder a disorder ina subject in need thereof. Some embodiments include administering acomposition described herein to a subject with the disorder. In someembodiments, the administration prevents, inhibits, or reverses thedisorder in the subject. In some embodiments, the composition prevents,inhibits, or reverses the disorder in the subject.

Some embodiments relate to a method of preventing a disorder a disorderin a subject in need thereof. Some embodiments relate to use of acomposition described herein in the method of preventing the disorder.Some embodiments include administering a composition described herein toa subject with the disorder. In some embodiments, the administrationprevents the disorder in the subject. In some embodiments, thecomposition prevents the disorder in the subject.

Some embodiments relate to a method of inhibiting a disorder a disorderin a subject in need thereof. Some embodiments relate to use of acomposition described herein in the method of inhibiting the disorder.Some embodiments include administering a composition described herein toa subject with the disorder. In some embodiments, the administrationinhibits the disorder in the subject. In some embodiments, thecomposition inhibits the disorder in the subject.

Some embodiments relate to a method of reversing a disorder a disorderin a subject in need thereof. Some embodiments relate to use of acomposition described herein in the method of reversing the disorder.Some embodiments include administering a composition described herein toa subject with the disorder. In some embodiments, the administrationreverses the disorder in the subject. In some embodiments, thecomposition reverses the disorder in the subject.

A. Disorders

Some embodiments of the methods described herein include treating adisorder in a subject in need thereof. In some embodiments, the disorderis a metabolic disorder. Examples of metabolic disorders includehyperlipidemia (for example, hypertriglyceridemia) and diabetes (forexample, type II diabetes). In some embodiments, the metabolic disordercomprises hyperlipidemia. In some embodiments, the metabolic disordercomprises hypertriglyceridemia. In some embodiments, the metabolicdisorder comprises familial chylomicronemia. In some embodiments, themetabolic disorder comprises hypertriglyceridemia in the context offamilial chylomicronemia. In some embodiments, the metabolic disordercomprises pancreatitis. In some embodiments, the metabolic disordercomprises acute pancreatitis. In some embodiments, the metabolicdisorder comprises hypertriglyceridemia and associated acutepancreatitis. In some embodiments, the metabolic disorder comprisesdiabetes. In some embodiments, the metabolic disorder comprises type 2diabetes. Some embodiments include a method of treating a metabolicdisorder in a subject in need thereof, the method comprisingadministering to the subject a composition comprising an oligonucleotidethat targets ANGPTL4.

In some embodiments, the disorder is a cardiometabolic disorder such asa cardiovascular disorder or a metabolic disorder. In some embodiments,the disorder is a cardiovascular disorder. Examples of cardiovasculardisorders include heart disease, myocardial infarction, angina (forexample, angina pectoris), and atherosclerosis. In some embodiments, thecardiovascular disorder comprises heart disease. In some embodiments,the cardiovascular disorder comprises myocardial infarction. In someembodiments, the cardiovascular disorder comprises angina pectoris. Insome embodiments, the cardiovascular disorder comprises atherosclerosis.Some embodiments include a method of treating a cardiovascular disorderin a subject in need thereof, the method comprising administering to thesubject a composition comprising an oligonucleotide that targetsANGPTL4.

B. Subjects

Some embodiments of the methods described herein include treatment of asubject. Examples of subjects include vertebrates, animals, mammals,dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans.In some embodiments, the subject is a vertebrate. In some embodiments,the subject is an animal. In some embodiments, the subject is a mammal.In some embodiments, the subject is a dog. In some embodiments, thesubject is a cat. In some embodiments, the subject is a cattle. In someembodiments, the subject is a mouse. In some embodiments, the subject isa rat. In some embodiments, the subject is a primate. In someembodiments, the subject is a monkey. In some embodiments, the subjectis an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat,a primate, or a monkey. In some embodiments, the subject is a human.

In some embodiments, the subject has a body mass index (BMI) of 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, or more, or a range defined by any two of theaforementioned integers. In some embodiments, the subject is overweight.In some embodiments, the subject has a BMI of 25 or more. In someembodiments, the subject has a BMI of 25-29. In some embodiments, thesubject is obese. In some embodiments, the subject has a BMI of 30 ormore. In some embodiments, the subject has a BMI of 30-39. In someembodiments, the subject has a BMI of 40-50. In some embodiments, thesubject has a BMI of 25-50.

In some embodiments, the subject is ≥90 years of age. In someembodiments, the subject is ≥85 years of age. In some embodiments, thesubject is ≥80 years of age. In some embodiments, the subject is ≥70years of age. In some embodiments, the subject is ≥60 years of age. Insome embodiments, the subject is ≥50 years of age. In some embodiments,the subject is ≥40 years of age. In some embodiments, the subject is ≥30years of age. In some embodiments, the subject is ≥20 years of age. Insome embodiments, the subject is ≥10 years of age. In some embodiments,the subject is ≥1 years of age. In some embodiments, the subject is ≥0years of age.

In some embodiments, the subject is ≤100 years of age. In someembodiments, the subject is ≤90 years of age. In some embodiments, thesubject is ≤85 years of age. In some embodiments, the subject is ≤80years of age. In some embodiments, the subject is ≤70 years of age. Insome embodiments, the subject is ≤60 years of age. In some embodiments,the subject is ≤50 years of age. In some embodiments, the subject is ≤40years of age. In some embodiments, the subject is ≤30 years of age. Insome embodiments, the subject is ≤20 years of age. In some embodiments,the subject is ≤10 years of age. In some embodiments, the subject is ≤1years of age.

In some embodiments, the subject is between 0 and 100 years of age. Insome embodiments, the subject is between 20 and 90 years of age. In someembodiments, the subject is between 30 and 80 years of age. In someembodiments, the subject is between 40 and 75 years of age. In someembodiments, the subject is between 50 and 70 years of age. In someembodiments, the subject is between 40 and 85 years of age.

C. Baseline Measurements

Some embodiments of the methods described herein include obtaining abaseline measurement from a subject. For example, in some embodiments, abaseline measurement is obtained from the subject prior to treating thesubject.

In some embodiments, the baseline measurement is obtained by performingan assay such as an immunoassay, a colorimetric assay, or a fluorescenceassay, on the sample obtained from the subject. In some embodiments, thebaseline measurement is obtained by an immunoassay, a colorimetricassay, or a fluorescence assay. In some embodiments, the baselinemeasurement is obtained by PCR.

In some embodiments, the baseline measurement is a baseline triglyceridemeasurement. In some embodiments, the baseline triglyceride measurementis a baseline triglyceride concentration (for example, mg/dL). In someembodiments, the baseline triglyceride measurement is a baselinecirculating triglyceride measurement. In some embodiments, the baselinetriglyceride measurement is obtained by an assay such as an immunoassay,a colorimetric assay, or a fluorescence assay.

In some embodiments, the baseline measurement is a baseline cholesterolmeasurement. In some embodiments, the baseline cholesterol measurementis a baseline cholesterol concentration. In some embodiments, thebaseline cholesterol concentration is a baseline total cholesterolconcentration. In some embodiments, the baseline cholesterol measurementis a baseline circulating cholesterol measurement. In some embodiments,the baseline cholesterol measurement is a baseline low densitylipoprotein (LDL) measurement. In some embodiments, the baselinecholesterol measurement is a baseline very low density lipoprotein(VLDL) measurement. In some embodiments, the baseline cholesterolmeasurement is obtained by an assay such as an immunoassay, acolorimetric assay, or a fluorescence assay.

In some embodiments, the baseline measurement is a baseline HDLmeasurement. In some embodiments, the baseline HDL measurement is abaseline HDL concentration. In some embodiments, the baseline HDLmeasurement is indicated relative to a baseline total cholesterolmeasurement. In some embodiments, the baseline HDL measurement is abaseline circulating HDL measurement. In some embodiments, the baselineHDL measurement is obtained by an assay such as an immunoassay, acolorimetric assay, or a fluorescence assay.

In some embodiments, the baseline measurement is a baseline glucosemeasurement. In some embodiments, the baseline glucose measurement is abaseline glucose concentration (for example, mg/dL). In someembodiments, the baseline glucose measurement comprises a baselineglucose concentration. In some embodiments, the baseline glucosemeasurement is a baseline circulating glucose measurement. In someembodiments, the baseline glucose measurement is obtained by an assaysuch as an immunoassay, a colorimetric assay, or a fluorescence assay.In some embodiments, the baseline glucose measurement is obtained

In some embodiments, the baseline glucose measurement comprises abaseline glucose tolerance test. In some embodiments, the baselineglucose tolerance test comprises administering glucose to the subject,and then obtaining multiple baseline glucose measurements over timeafter administering the glucose to the subject. In some embodiments, theglucose is administered orally. In some embodiments, the glucose isadministered by injection. In some embodiments, the multiple baselineglucose measurements are integrated into a baseline glucose area underthe curve (AUC) measurement. In some embodiments, the baseline glucosetolerance test is performed on the subject in a fasted state such asafter an overnight fast. In some embodiments, the baseline glucosemeasurement comprises a baseline glucose measurement other than abaseline glucose tolerance test.

In some embodiments, the baseline measurement is a baseline insulinmeasurement. In some embodiments, the baseline insulin measurement is abaseline insulin sensitivity measurement. In some embodiments, thebaseline insulin sensitivity measurement is obtained using a glucoseclamp technique such as a hyperinsulinemic euglycemic clamp. In someembodiments, the baseline insulin measurement is a baseline insulinconcentration. In some embodiments, the baseline insulin measurementcomprises a baseline insulin concentration. In some embodiments, thebaseline insulin measurement is a baseline circulating insulinmeasurement. In some embodiments, the baseline insulin measurement isobtained by an assay such as an immunoassay (for example, an ELISA or animmunoblot), a colorimetric assay, or a fluorescence assay. In someembodiments, the baseline insulin sensitivity measurement comprises abaseline glucose tolerance test. In some embodiments, the baselineinsulin sensitivity measurement comprises a baseline insulin sensitivitymeasurement other than a baseline glucose tolerance test.

In some embodiments, the baseline insulin measurement comprises abaseline insulin response test. In some embodiments, the baselineinsulin response test comprises administering glucose to the subject andthen obtaining multiple baseline insulin measurements over time afteradministering the glucose to the subject. In some embodiments, theglucose is administered orally. In some embodiments, the glucose isadministered by injection. In some embodiments, the multiple baselineinsulin measurements are integrated into a baseline insulin AUCmeasurement. In some embodiments, the baseline insulin response test isperformed on the subject in a fasted state such as after an overnightfast.

In some embodiments, the baseline insulin measurement comprises abaseline glucose response test. In some embodiments, the baselineglucose response test comprises administering insulin to the subject,and then obtaining multiple baseline glucose measurements over timeafter administering the insulin to the subject. In some embodiments, theinsulin is administered by injection. In some embodiments, the multiplebaseline glucose measurements are integrated into a baseline glucose AUCmeasurement. In some embodiments, the multiple baseline glucosemeasurements are obtained with a glucometer. In some embodiments, theglucose response test is performed on the subject in a fasted state suchas after an overnight fast. In some embodiments, the glucose responsetest is performed on the subject after administering food, drink, orglucose to the subject.

In some embodiments, the baseline measurement is a baseline ANGPTL4protein measurement. In some embodiments, the baseline ANGPTL4 proteinmeasurement comprises a baseline ANGPTL4 protein level. In someembodiments, the baseline ANGPTL4 protein level is indicated as a massor percentage of ANGPTL4 protein per sample weight. In some embodiments,the baseline ANGPTL4 protein level is indicated as a mass or percentageof ANGPTL4 protein per sample volume. In some embodiments, the baselineANGPTL4 protein level is indicated as a mass or percentage of ANGPTL4protein per total protein within the sample. In some embodiments, thebaseline ANGPTL4 protein measurement is a baseline cell (e.g.hepatocyte) ANGPTL4 protein measurement. In some embodiments, thebaseline ANGPTL4 protein measurement is a baseline tissue (e.g. livertissue) ANGPTL4 protein measurement. In some embodiments, the baselineANGPTL4 protein measurement is a baseline circulating ANGPTL4 proteinmeasurement. In some embodiments, the baseline ANGPTL4 proteinmeasurement is obtained by an assay such as an immunoassay, acolorimetric assay, or a fluorescence assay.

In some embodiments, the baseline measurement is a baseline ANGPTL4 mRNAmeasurement. In some embodiments, the baseline ANGPTL4 mRNA measurementcomprises a baseline ANGPTL4 mRNA level. In some embodiments, thebaseline ANGPTL4 mRNA level is indicated as a mass or percentage ofANGPTL4 mRNA per sample weight. In some embodiments, the baselineANGPTL4 mRNA level is indicated as a mass or percentage of ANGPTL4 mRNAper sample volume. In some embodiments, the baseline ANGPTL4 mRNA levelis indicated as a mass or percentage of ANGPTL4 mRNA per total mRNAwithin the sample. In some embodiments, the baseline ANGPTL4 mRNA levelis indicated as a mass or percentage of ANGPTL4 mRNA per total nucleicacids within the sample. In some embodiments, the baseline ANGPTL4 mRNAlevel is indicated relative to another mRNA level, such as an mRNA levelof a housekeeping gene, within the sample. In some embodiments, thebaseline ANGPTL4 mRNA measurement is obtained by an assay such as apolymerase chain reaction (PCR) assay. In some embodiments, the PCRcomprises quantitative PCR (qPCR). In some embodiments, the PCRcomprises reverse transcription of the ANGPTL4 mRNA.

Some embodiments of the methods described herein include obtaining asample from a subject. In some embodiments, the baseline measurement isobtained in a sample obtained from the subject. In some embodiments, thesample is obtained from the subject prior to administration or treatmentof the subject with a composition described herein. In some embodiments,a baseline measurement is obtained in a sample obtained from the subjectprior to administering the composition to the subject. In someembodiments, the sample is obtained from the subject in a fasted state.In some embodiments, the sample is obtained from the subject after anovernight fasting period. In some embodiments, the sample is obtainedfrom the subject in a fed state.

In some embodiments, the sample comprises a fluid. In some embodiments,the sample is a fluid sample. In some embodiments, the sample is ablood, plasma, or serum sample. In some embodiments, the samplecomprises blood. In some embodiments, the sample is a blood sample. Insome embodiments, the sample is a whole-blood sample. In someembodiments, the blood is fractionated or centrifuged. In someembodiments, the sample comprises plasma. In some embodiments, thesample is a plasma sample. In some embodiments, the sample comprisesserum. In some embodiments, the sample is a serum sample. For example,the baseline triglyceride 33measurement, the baseline cholesterolmeasurement, the baseline HDL measurement, the baseline glucosemeasurement, the baseline insulin measurement, or the baseline ANGPTL4protein measurement may be obtained in a serum sample from the patient.

In some embodiments, the sample comprises a tissue. In some embodiments,the sample is a tissue sample. In some embodiments, the sample comprisesliver tissue. In some embodiments, the sample is a liver sample. In someembodiments, the sample comprises adipose tissue. In some embodiments,the sample is an adipose sample. In some embodiments, the samplecomprises pancreatic tissue. In some embodiments, the sample comprises apancreas sample. For example, the baseline ANGPTL4 mRNA measurement, orthe baseline ANGPTL4 protein measurement, may be obtained in a liver oradipose sample from the patient. In some embodiments, the samplecomprises intestinal tissue such as small intestinal tissue. In someembodiments, the sample is a small intestine sample. In someembodiments, the sample comprises lymph node tissue such as mesentericlymph node tissue. In some embodiments, the sample is a mesenteric lymphnode sample. In some embodiments, the sample comprises cardiac tissuesuch as ventricular or atrial tissue. In some embodiments, the sample isa cardiac sample. In some embodiments, the tissue sample comprisesliver, adipose, small intestine, mesenteric lymph node, or cardiactissue. In some embodiments, the tissue sample comprises brown adiposetissue, white adipose tissue, kidney tissue, or muscle tissue.

D. Effects

In some embodiments, the composition or administration of thecomposition affects a measurement such as a triglyceride measurement, acholesterol measurement, an HDL measurement, a glucose measurement, aninsulin measurement, an ANGPTL4 protein measurement (for example,circulating or tissue ANGPTL4 protein levels), or an ANGPTL4 mRNAmeasurement, relative to the baseline measurement.

Some embodiments of the methods described herein include obtaining themeasurement from a subject. For example, the measurement may be obtainedfrom the subject after treating the subject. In some embodiments, themeasurement is obtained in a second sample (such as a fluid or tissuesample described herein) obtained from the subject after the compositionis administered to the subject. In some embodiments, the measurement isan indication that the disorder has been treated.

In some embodiments, the measurement is obtained by an assay asdescribed herein. For example, the assay may comprise an immunoassay, acolorimetric assay, a fluorescence assay, or a PCR assay.

In some embodiments, the measurement is obtained within 1 week, within 2weeks, within 3 weeks, within 1 month, within 2 months, within 3 months,within 6 months, within 1 year, within 2 years, within 3 years, within 4years, or within 5 years after the administration of the composition. Insome embodiments, the measurement is obtained after 1 week, after 2weeks, after 3 weeks, after 1 month, after 2 months, after 3 months,after 6 months, after 1 year, after 2 years, after 3 years, after 4years, or after 5 years, following the administration of thecomposition.

In some embodiments, the measurement is a triglyceride measurement. Insome embodiments, the triglyceride measurement is a triglycerideconcentration (for example, mg/dL). In some embodiments, thetriglyceride measurement is a circulating triglyceride measurement. Insome embodiments, the triglyceride measurement is obtained by an assaysuch as an immunoassay, a colorimetric assay, or a fluorescence assay.

In some embodiments, the composition reduces the triglyceridemeasurement relative to the baseline triglyceride measurement. In someembodiments, the composition reduces circulating triglycerides relativeto the baseline triglyceride measurement. In some embodiments, thereduced triglycerides are measured in a second sample obtained from thesubject after administering the composition to the subject.

In some embodiments, the triglyceride measurement is decreased by about2.5% or more, about 5% or more, or about 7.5% or more, relative to thebaseline triglyceride measurement. In some embodiments, the triglyceridemeasurement is decreased by about 10% or more, relative to the baselinetriglyceride measurement. In some embodiments, the triglyceridemeasurement is decreased by about 20% or more, about 30% or more, about40% or more, about 50% or more, about 60% or more, about 70% or more,about 80% or more, about 90% or more, or about 100%, relative to thebaseline triglyceride measurement. In some embodiments, the triglyceridemeasurement is decreased by no more than about 2.5%, no more than about5%, or no more than about 7.5%, relative to the baseline triglyceridemeasurement. In some embodiments, the triglyceride measurement isdecreased by no more than about 10%, relative to the baselinetriglyceride measurement. In some embodiments, the triglyceridemeasurement is decreased by no more than about 20%, no more than about30%, no more than about 40%, no more than about 50%, no more than about60%, no more than about 70%, no more than about 80%, no more than about90%, or no more than about 100% relative to the baseline triglyceridemeasurement. In some embodiments, the triglyceride measurement isdecreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 100%, or by a range defined by any of the two aforementionedpercentages.

In some embodiments, the measurement is a cholesterol measurement. Insome embodiments, the cholesterol measurement is a total cholesterolmeasurement. In some embodiments, the cholesterol measurement is acholesterol concentration. In some embodiments, the cholesterolconcentration is a total cholesterol concentration. In some embodiments,the cholesterol measurement is a circulating cholesterol measurement. Insome embodiments, the cholesterol measurement is a low densitylipoprotein (LDL) measurement. In some embodiments, the cholesterolmeasurement is a very low density lipoprotein (VLDL) measurement. Insome embodiments, the cholesterol measurement is obtained by an assaysuch as an immunoassay, a colorimetric assay, or a fluorescence assay.

In some embodiments, the composition reduces the cholesterol measurementrelative to the baseline cholesterol measurement. In some embodiments,the composition reduces circulating cholesterol relative to the baselinecholesterol measurement. In some embodiments, the reduced cholesterol ismeasured in a second sample obtained from the subject afteradministering the composition to the subject.

In some embodiments, the cholesterol measurement is decreased by about2.5% or more, about 5% or more, or about 7.5% or more, relative to thebaseline cholesterol measurement. In some embodiments, the cholesterolmeasurement is decreased by about 10% or more, relative to the baselinecholesterol measurement. In some embodiments, the cholesterolmeasurement is decreased by about 20% or more, about 30% or more, about40% or more, about 50% or more, about 60% or more, about 70% or more,about 80% or more, about 90% or more, or about 100%, relative to thebaseline cholesterol measurement. In some embodiments, the cholesterolis decreased by no more than about 2.5%, no more than about 5%, or nomore than about 7.5%, relative to the baseline cholesterol measurement.In some embodiments, the cholesterol is decreased by no more than about10%, relative to the baseline cholesterol measurement. In someembodiments, the cholesterol is decreased by no more than about 20%, nomore than about 30%, no more than about 40%, no more than about 50%, nomore than about 60%, no more than about 70%, no more than about 80%, nomore than about 90%, or no more than about 100% relative to the baselinecholesterol measurement. In some embodiments, the cholesterolmeasurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 100%, or by a range defined by any of the twoaforementioned percentages.

In some embodiments, the measurement is an HDL measurement. In someembodiments, the HDL measurement is an HDL concentration. In someembodiments, the HDL measurement is indicated relative to a totalcholesterol measurement. In some embodiments, the HDL measurement is acirculating HDL measurement. In some embodiments, the HDL measurement isobtained by an assay such as an immunoassay, a colorimetric assay, or afluorescence assay.

In some embodiments, the composition reduces the HDL measurementrelative to the baseline HDL measurement. In some embodiments, thecomposition increases circulating HDL relative to the baseline HDLmeasurement. In some embodiments, the increased HDL is measured in asecond sample obtained from the subject after administering thecomposition to the subject.

In some embodiments, the HDL measurement is increased by about 2.5% ormore, about 5% or more, or about 7.5% or more, relative to the baselineHDL measurement. In some embodiments, the HDL measurement is increasedby about 10% or more, relative to the baseline HDL measurement. In someembodiments, the HDL measurement is increased by about 20% or more,about 30% or more, about 40% or more, about 50% or more, about 60% ormore, about 70% or more, about 80% or more, about 90% or more, or about100% or more relative to the baseline HDL measurement. In someembodiments, the HDL measurement is increased by about 200% or more,about 300% or more, about 400% or more, about 500% or more, about 600%or more, about 700% or more, about 800% or more, about 900% or more, orabout 1000% or more, relative to the baseline HDL measurement. In someembodiments, the HDL measurement is increased by no more than about2.5%, no more than about 5%, or no more than about 7.5%, relative to thebaseline HDL measurement. In some embodiments, the HDL measurement isincreased by no more than about 10%, relative to the baseline HDLmeasurement. In some embodiments, the HDL measurement is increased by nomore than about 20%, no more than about 30%, no more than about 40%, nomore than about 50%, no more than about 60%, no more than about 70%, nomore than about 80%, no more than about 90%, or no more than about 100%relative to the baseline HDL measurement. In some embodiments, the HDLmeasurement is increased by no more than about 200%, no more than about300%, no more than about 400%, no more than about 500%, no more thanabout 600%, no more than about 700%, no more than about 800%, no morethan about 900%, or no more than about 1000%, relative to the baselineHDL measurement. In some embodiments, the HDL measurement is increasedby 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%,200% 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or by a rangedefined by any of the two aforementioned percentages.

In some embodiments, the measurement is a glucose measurement. In someembodiments, the glucose measurement comprises a glucose concentration(for example, mg/dL). In some embodiments, the glucose measurement is aglucose concentration. In some embodiments, the glucose measurement is acirculating glucose measurement. In some embodiments, the glucosemeasurement is obtained by an assay such as an immunoassay, acolorimetric assay, or a fluorescence assay. In some embodiments, theglucose measurement is obtained using a glucometer.

In some embodiments, the glucose measurement comprises a glucosetolerance test. In some embodiments, the glucose tolerance testcomprises administering glucose to the subject, and then obtainingmultiple glucose measurements over time after administering the glucoseto the subject. In some embodiments, the glucose is administered orally.In some embodiments, the glucose is administered by injection. In someembodiments, the multiple glucose measurements are integrated into aglucose area under the curve (AUC) measurement. In some embodiments, theglucose tolerance test is performed on the subject in a fasted statesuch as after an overnight fast. In some embodiments, the glucosemeasurement comprises a glucose measurement other than a glucosetolerance test.

In some embodiments, the composition reduces the glucose measurementrelative to the baseline glucose measurement. In some embodiments, thecomposition reduces circulating glucose relative to the baseline glucosemeasurement. In some embodiments, the reduced glucose is measured in asecond sample obtained from the subject after administering thecomposition to the subject. In some embodiments, the composition reducesone or more of the multiple glucose measurements of the glucosetolerance test relative to one or more of the multiple glucosemeasurements of the baseline glucose tolerance test. In someembodiments, the composition reduces the glucose AUC measurementrelative to the baseline glucose AUC measurement.

In some embodiments, the glucose measurement is decreased by about 2.5%or more, about 5% or more, or about 7.5% or more, relative to thebaseline glucose measurement. In some embodiments, the glucosemeasurement is decreased by about 10% or more, relative to the baselineglucose measurement. In some embodiments, the glucose measurement isdecreased by about 20% or more, about 30% or more, about 40% or more,about 50% or more, about 60% or more, about 70% or more, about 80% ormore, about 90% or more, or about 100%, relative to the baseline glucosemeasurement. In some embodiments, the glucose is decreased by no morethan about 2.5%, no more than about 5%, or no more than about 7.5%,relative to the baseline glucose measurement. In some embodiments, theglucose is decreased by no more than about 10%, relative to the baselineglucose measurement. In some embodiments, the glucose is decreased by nomore than about 20%, no more than about 30%, no more than about 40%, nomore than about 50%, no more than about 60%, no more than about 70%, nomore than about 80%, no more than about 90%, or no more than about 100%relative to the baseline glucose measurement. In some embodiments, theglucose measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 100%, or by a range defined by any of the twoaforementioned percentages.

In some embodiments, the measurement is an insulin measurement. In someembodiments, the insulin measurement is an insulin sensitivitymeasurement. In some embodiments, the insulin sensitivity measurement isobtained using a glucose clamp technique such as a hyperinsulinemiceuglycemic clamp. In some embodiments, the insulin measurement comprisesan insulin concentration. In some embodiments, the insulin measurementis an insulin concentration. In some embodiments, the insulinmeasurement is a circulating insulin measurement. In some embodiments,the insulin measurement is obtained by an assay such as an immunoassay,a colorimetric assay, or a fluorescence assay. In some embodiments, theinsulin sensitivity measurement comprises a glucose tolerance test. Insome embodiments, the insulin sensitivity measurement comprises aninsulin sensitivity measurement other than a glucose tolerance test.

In some embodiments, the insulin measurement comprises an insulinresponse test. In some embodiments, the insulin response test comprisesadministering glucose to the subject, and then obtaining multipleinsulin measurements over time after administering the glucose to thesubject. In some embodiments, the glucose is administered orally. Insome embodiments, the glucose is administered by injection. In someembodiments, the multiple insulin measurements are integrated into aninsulin AUC measurement. In some embodiments, the insulin response testis performed on the subject in a fasted state such as after an overnightfast.

In some embodiments, the insulin measurement comprises a glucoseresponse test. In some embodiments, the glucose response test comprisesadministering insulin to the subject, and then obtaining multipleglucose measurements over time after administering the insulin to thesubject. In some embodiments, the insulin is administered by injection.In some embodiments, the multiple glucose measurements are integratedinto a glucose AUC measurement. In some embodiments, the multipleglucose measurements are measured with a glucometer. In someembodiments, the glucose response test is performed on the subject in afasted state such as after an overnight fast. In some embodiments, theglucose response test is performed on the subject after administeringfood, drink, or glucose to the subject.

In some embodiments, the composition increases the insulin sensitivityrelative to the baseline insulin sensitivity measurement. In someembodiments, the insulin sensitivity is increased by about 2.5% or more,about 5% or more, or about 7.5% or more, relative to the baselineinsulin sensitivity measurement. In some embodiments, the insulinsensitivity is increased by about 10% or more, relative to the baselineinsulin sensitivity measurement. In some embodiments, the insulinsensitivity is increased by about 20% or more, about 30% or more, about40% or more, about 50% or more, about 60% or more, about 70% or more,about 80% or more, about 90% or more, or about 100% or more relative tothe baseline insulin sensitivity measurement. In some embodiments, theinsulin sensitivity is increased by about 200% or more, about 300% ormore, about 400% or more, about 500% or more, about 600% or more, about700% or more, about 800% or more, about 900% or more, or about 1000% ormore, relative to the baseline insulin sensitivity measurement. In someembodiments, the insulin sensitivity is increased by no more than about2.5%, no more than about 5%, or no more than about 7.5%, relative to thebaseline insulin sensitivity measurement. In some embodiments, theinsulin sensitivity is increased by no more than about 10%, relative tothe baseline insulin sensitivity measurement. In some embodiments, theinsulin sensitivity is increased by no more than about 20%, no more thanabout 30%, no more than about 40%, no more than about 50%, no more thanabout 60%, no more than about 70%, no more than about 80%, no more thanabout 90%, or no more than about 100% relative to the baseline insulinsensitivity measurement. In some embodiments, the insulin sensitivity isincreased by no more than about 200%, no more than about 300%, no morethan about 400%, no more than about 500%, no more than about 600%, nomore than about 700%, no more than about 800%, no more than about 900%,or no more than about 1000%, relative to the baseline insulinsensitivity measurement. In some embodiments, the insulin sensitivity isincreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 100%, 200% 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or by arange defined by any of the two aforementioned percentages.

In some embodiments, the composition reduces the insulin measurementrelative to the baseline insulin measurement. In some embodiments, thecomposition reduces circulating insulin relative to the baseline insulinmeasurement. In some embodiments, the reduced insulin is measured in asecond sample obtained from the subject after administering thecomposition to the subject. In some embodiments, the composition reducesthe insulin AUC measurement relative to the baseline insulin AUCmeasurement.

In some embodiments, the insulin measurement is decreased by about 2.5%or more, about 5% or more, or about 7.5% or more, relative to thebaseline insulin measurement. In some embodiments, the insulinmeasurement is decreased by about 10% or more, relative to the baselineinsulin measurement. In some embodiments, the insulin measurement isdecreased by about 20% or more, about 30% or more, about 40% or more,about 50% or more, about 60% or more, about 70% or more, about 80% ormore, about 90% or more, or about 100%, relative to the baseline insulinmeasurement. In some embodiments, the insulin is decreased by no morethan about 2.5%, no more than about 5%, or no more than about 7.5%,relative to the baseline insulin measurement. In some embodiments, theinsulin is decreased by no more than about 10%, relative to the baselineinsulin measurement. In some embodiments, the insulin is decreased by nomore than about 20%, no more than about 30%, no more than about 40%, nomore than about 50%, no more than about 60%, no more than about 70%, nomore than about 80%, no more than about 90%, or no more than about 100%relative to the baseline insulin measurement. In some embodiments, theinsulin measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 100%, or by a range defined by any of the twoaforementioned percentages.

In some embodiments, the measurement is an ANGPTL4 protein measurement.In some embodiments, the ANGPTL4 protein measurement comprises anANGPTL4 protein level. In some embodiments, the ANGPTL4 protein level isindicated as a mass or percentage of ANGPTL4 protein per sample weight.In some embodiments, the ANGPTL4 protein level is indicated as a mass orpercentage of ANGPTL4 protein per sample volume. In some embodiments,the ANGPTL4 protein level is indicated as a mass or percentage ofANGPTL4 protein per total protein within the sample. In someembodiments, the ANGPTL4 protein measurement is a cell (e.g. hepatocyte)ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 proteinmeasurement is a tissue (e.g. liver tissue) ANGPTL4 protein measurement.In some embodiments, the ANGPTL4 protein measurement is a circulatingANGPTL4 protein measurement. In some embodiments, the baseline ANGPTL4protein measurement is obtained by an assay such as an immunoassay, acolorimetric assay, or a fluorescence assay.

In some embodiments, the composition reduces the ANGPTL4 proteinmeasurement relative to the baseline ANGPTL4 protein measurement. Insome embodiments, the composition reduces circulating ANGPTL4 proteinlevels relative to the baseline ANGPTL4 protein measurement. In someembodiments, the composition reduces tissue ANGPTL4 protein levels (suchas liver tissue ANGPTL protein levels) relative to the baseline ANGPTL4protein measurement. In some embodiments, the composition reduces cellANGPTL4 protein levels (such as hepatocyte ANGPTL protein levels)relative to the baseline ANGPTL4 protein measurement. In someembodiments, the reduced ANGPTL4 protein levels are measured in a secondsample obtained from the subject after administering the composition tothe subject.

In some embodiments, the ANGPTL4 protein measurement is decreased byabout 2.5% or more, about 5% or more, or about 7.5% or more, relative tothe baseline ANGPTL4 protein measurement. In some embodiments, theANGPTL4 protein measurement is decreased by about 10% or more, relativeto the baseline ANGPTL4 protein measurement. In some embodiments, theANGPTL4 protein measurement is decreased by about 20% or more, about 30%or more, about 40% or more, about 50% or more, about 60% or more, about70% or more, about 80% or more, about 90% or more, or about 100%,relative to the baseline ANGPTL4 protein measurement. In someembodiments, the ANGPTL4 protein measurement is decreased by no morethan about 2.5%, no more than about 5%, or no more than about 7.5%,relative to the baseline ANGPTL4 protein measurement. In someembodiments, the ANGPTL4 protein measurement is decreased by no morethan about 10%, relative to the baseline ANGPTL4 protein measurement. Insome embodiments, the ANGPTL4 protein measurement is decreased by nomore than about 20%, no more than about 30%, no more than about 40%, nomore than about 50%, no more than about 60%, no more than about 70%, nomore than about 80%, no more than about 90%, or no more than about 100%relative to the baseline ANGPTL4 protein measurement. In someembodiments, the ANGPTL4 protein measurement is decreased by 2.5%, 5%,7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or by a rangedefined by any of the two aforementioned percentages.

In some embodiments, the measurement is an ANGPTL4 mRNA measurement. Insome embodiments, the ANGPTL4 mRNA measurement comprises an ANGPTL4 mRNAlevel. In some embodiments, the ANGPTL4 mRNA level is indicated as amass or percentage of ANGPTL4 mRNA per sample weight. In someembodiments, the ANGPTL4 mRNA level is indicated as a mass or percentageof ANGPTL4 mRNA per sample volume. In some embodiments, the ANGPTL4 mRNAlevel is indicated as a mass or percentage of ANGPTL4 mRNA per totalmRNA within the sample. In some embodiments, the ANGPTL4 mRNA level isindicated as a mass or percentage of ANGPTL4 mRNA per total nucleicacids within the sample. In some embodiments, the ANGPTL4 mRNA level isindicated relative to another mRNA level, such as an mRNA level of ahousekeeping gene, within the sample. In some embodiments, the ANGPTL4mRNA measurement is obtained by an assay such as a PCR assay. In someembodiments, the PCR comprises qPCR. In some embodiments, the PCRcomprises reverse transcription of the ANGPTL4 mRNA.

In some embodiments, the composition reduces the ANGPTL4 mRNAmeasurement relative to the baseline ANGPTL4 mRNA measurement. In someembodiments, the ANGPTL4 mRNA measurement is obtained in a second sampleobtained from the subject after administering the composition to thesubject. In some embodiments, the composition reduces ANGPTL4 mRNAlevels relative to the baseline ANGPTL4 mRNA levels. In someembodiments, the reduced ANGPTL4 mRNA levels are measured in a secondsample obtained from the subject after administering the composition tothe subject. In some embodiments, the second sample is a liver sample.In some embodiments, the second sample is an adipose sample.

In some embodiments, the ANGPTL4 mRNA measurement is reduced by about2.5% or more, about 5% or more, or about 7.5% or more, relative to thebaseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNAmeasurement is decreased by about 10% or more, relative to the baselineANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNAmeasurement is decreased by about 20% or more, about 30% or more, about40% or more, about 50% or more, about 60% or more, about 70% or more,about 80% or more, about 90% or more, or about 100%, relative to thebaseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNAmeasurement is decreased by no more than about 2.5%, no more than about5%, or no more than about 7.5%, relative to the baseline ANGPTL4 mRNAmeasurement. In some embodiments, the ANGPTL4 mRNA measurement isdecreased by no more than about 10%, relative to the baseline ANGPTL4mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement isdecreased by no more than about 20%, no more than about 30%, no morethan about 40%, no more than about 50%, no more than about 60%, no morethan about 70%, no more than about 80%, no more than about 90%, or nomore than about 100% relative to the baseline ANGPTL4 mRNA measurement.In some embodiments, the ANGPTL4 mRNA measurement is decreased by 2.5%,5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or by arange defined by any of the two aforementioned percentages.

III. Definitions

Unless defined otherwise, all terms of art, notations and othertechnical and scientific terms or terminology used herein are intendedto have the same meaning as is commonly understood by one of ordinaryskill in the art to which the claimed subject matter pertains. In somecases, terms with commonly understood meanings are defined herein forclarity and/or for ready reference, and the inclusion of suchdefinitions herein should not necessarily be construed to represent asubstantial difference over what is generally understood in the art.

Throughout this application, various embodiments may be presented in arange format. It should be understood that the description in rangeformat is merely for convenience and brevity and should not be construedas an inflexible limitation on the scope of the disclosure. Accordingly,the description of a range should be considered to have specificallydisclosed all the possible subranges as well as individual numericalvalues within that range. For example, description of a range such asfrom 1 to 6 should be considered to have specifically disclosedsubranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4,from 2 to 6, from 3 to 6 etc., as well as individual numbers within thatrange, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of thebreadth of the range.

As used in the specification and claims, the singular forms “a”, “an”and “the” include plural references unless the context clearly dictatesotherwise. For example, the term “a sample” includes a plurality ofsamples, including mixtures thereof.

The terms “determining,” “measuring,” “evaluating,” “assessing,”“assaying,” and “analyzing” are often used interchangeably herein torefer to forms of measurement. The terms include determining if anelement is present or not (for example, detection). These terms caninclude quantitative, qualitative or quantitative and qualitativedeterminations. Assessing can be relative or absolute. “Detecting thepresence of” can include determining the amount of something present inaddition to determining whether it is present or absent depending on thecontext.

The terms “subject,” and “patient” may be used interchangeably herein. A“subject” can be a biological entity containing expressed geneticmaterials. The biological entity can be a plant, animal, ormicroorganism, including, for example, bacteria, viruses, fungi, andprotozoa. The subject can be a mammal. The mammal can be a human. Thesubject may be diagnosed or suspected of being at high risk for adisease. In some cases, the subject is not necessarily diagnosed orsuspected of being at high risk for the disease.

As used herein, the term “about” a number refers to that number plus orminus 10% of that number. The term “about” a range refers to that rangeminus 10% of its lowest value and plus 10% of its greatest value.

As used herein, the terms “treatment” or “treating” are used inreference to a pharmaceutical or other intervention regimen forobtaining beneficial or desired results in the recipient. Beneficial ordesired results include but are not limited to a therapeutic benefitand/or a prophylactic benefit. A therapeutic benefit may refer toeradication or amelioration of symptoms or of an underlying disorderbeing treated. Also, a therapeutic benefit can be achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the subject, notwithstanding that the subject may still beafflicted with the underlying disorder. A prophylactic effect includesdelaying, preventing, or eliminating the appearance of a disease orcondition, delaying or eliminating the onset of symptoms of a disease orcondition, slowing, halting, or reversing the progression of a diseaseor condition, or any combination thereof. For prophylactic benefit, asubject at risk of developing a particular disease, or to a subjectreporting one or more of the physiological symptoms of a disease mayundergo treatment, even though a diagnosis of this disease may not havebeen made.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

IV. Sequence Information

Some embodiments include one or more nucleic acid sequences in thefollowing table:

TABLE 1 Sequence Information SEQ ID NO: Description 1-1854 & ANGPTL4siRNA oligonucleotide 13970-13977 sense strand sequences 1855-3708 &ANGPTL4 siRNA oligonucleotide 13978-13985 antisense strand sequences3709-13934 ANGPTL4 ASO sequences 13935 Full-length human ANGPTL4 humanmRNA sequence (GenBank Acc.# NM_139314.3) 13936 Full-length ANGPTL4human pre-mRNA sequence (NC_00019.10: 8364129-8374373) 13937-13944Sequences for siRNA sense strands targeting mouse ANGPTL4 13945-13952Sequences for siRNA antisense strands targeting mouse ANGPTL4 13953Non-targeting control ASO oligonucleotide sequence 13954-13959Modification pattern 1S to 6S 13960-13968 Modification pattern 1AS to9AS 13969 Modification pattern ASO1 13986-14133 Modified ANGPTL4 siRNAoligonucleotide sense strand sequences 14134-14288 Modified ANGPTL4siRNA oligonucleotide antisense strand sequences 14289-14290 ETD00971sense and antisense strands 14291-14292 ETD00959 sense and antisensestrands

V. Embodiments

Some embodiments include one or more of the following:

1. A composition comprising an oligonucleotide that targetsAngiopoietin-like 4 (ANGPTL4) and when administered to a subject in aneffective amount decreases circulating triglycerides.

2. The composition of embodiment 1, wherein the triglycerides aredecreased by about 10% or more, as compared to prior to administration.

3. A composition comprising an oligonucleotide that targets ANGPTL4 andwhen administered to a subject in an effective amount decreasescirculating total cholesterol.

4. The composition of embodiment 3, wherein the total cholesterol isdecreased by about 10% or more, as compared to prior to administration.

5. A composition comprising an oligonucleotide that targets ANGPTL4 andwhen administered to a subject in an effective amount increasescirculating high-density lipoproteins (HDL).

6. The composition of embodiment 5, wherein the HDL are increased byabout 10% or more, as compared to prior to administration.

7. A composition comprising an oligonucleotide that targets ANGPTL4 andwhen administered to a subject in an effective amount decreasescirculating glucose.

8. The composition of embodiment 7, wherein the glucose is decreased byabout 10% or more, as compared to prior to administration.

9. A composition comprising an oligonucleotide that targets ANGPTL4 andwhen administered to a subject in an effective amount increases insulinsensitivity.

10. The composition of embodiment 9, wherein the insulin sensitivity isincreased by about 10% or more, as compared to prior to administration.

11. The composition of any one of embodiments 1-10, wherein theoligonucleotide comprises a modified internucleoside linkage.

12. The composition of embodiment 11, wherein the modifiedinternucleoside linkage comprises alkylphosphonate, phosphorothioate,methylphosphonate, phosphorodithioate, alkylphosphonothioate,phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate,or carboxymethyl ester, or a combination thereof.

13. The composition of embodiment 11, wherein the modifiedinternucleoside linkage comprises one or more phosphorothioate linkages.

14. The composition of any one of embodiments 1-13, wherein theoligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20 modified internucleoside linkages.

15. The composition of any one of embodiments 1-14, wherein theoligonucleotide comprises 2 or more modified internucleoside linkages, 3or more modified internucleoside linkages, 4 or more modifiedinternucleoside linkages, 5 or more modified internucleoside linkages, 6or more modified internucleoside linkages, 7 or more modifiedinternucleoside linkages, 8 or more modified internucleoside linkages, 9or more modified internucleoside linkages, 10 or more modifiedinternucleoside linkages, 11 or more modified internucleoside linkages,12 or more modified internucleoside linkages, 13 or more modifiedinternucleoside linkages, 14 or more modified internucleoside linkages,15 or more modified internucleoside linkages, 16 or more modifiedinternucleoside linkages, 17 or more modified internucleoside linkages,18 or more modified internucleoside linkages, 19 or more modifiedinternucleoside linkages, or 20 or more modified internucleosidelinkages.

16. The composition of any one of embodiments 1-15, wherein theoligonucleotide comprises a modified nucleoside.

17. The composition of embodiment 16, wherein the modified nucleosidecomprises a locked nucleic acid (LNA), hexitol nucleic acid (HLA),cyclohexene nucleic acid (CeNA), 2′-methoxyethyl, 2′-O-alkyl,2′-O-allyl, 2′-O-allyl, 2′-fluoro, or 2′-deoxy, or a combinationthereof.

18. The composition of embodiment 16, wherein the modified nucleosidecomprises a LNA.

19. The composition of embodiment 16, wherein the modified nucleosidecomprises a 2′,4′ constrained ethyl nucleic acid.

20. The composition of embodiment 16, wherein the modified nucleosidecomprises a 2′-O-methyl nucleoside, 2′-deoxyfluoro nucleoside,2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl(2′-O-AP) nucleoside, or 2′-ara-F, or a combination thereof.

21. The composition of embodiment 16, wherein the modified nucleosidecomprises one or more 2′fluoro modified nucleosides.

22. The composition of embodiment 16, wherein the modified nucleosidecomprises a 2′ O-alkyl modified nucleoside.

23. The composition of embodiment 16, wherein the oligonucleotidecomprises a lipid attached at a 3′ or 5′ terminus of theoligonucleotide.

24. The composition of embodiment 23, wherein the lipid comprisescholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl,docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or acombination thereof.

25. The composition of any one of embodiments 1-24, wherein theoligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, or 21 modified nucleosides.

26. The composition of any one of embodiments 1-25, wherein theoligonucleotide comprises 2 or more modified nucleosides, 3 or moremodified nucleosides, 4 or more modified nucleosides, 5 or more modifiednucleosides, 6 or more modified nucleosides, 7 or more modifiednucleosides, 8 or more modified nucleosides, 9 or more modifiednucleosides, 10 or more modified nucleosides, 11 or more modifiednucleosides, 12 or more modified nucleosides, 13 or more modifiednucleosides, 14 or more modified nucleosides, 15 or more modifiednucleosides, 16 or more modified nucleosides, 17 or more modifiednucleosides, 18 or more modified nucleosides, 19 or more modifiednucleosides, 20 or more modified nucleosides, or 21 or more modifiednucleosides.

27. The composition of any one of embodiments 1-26, wherein theoligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand forhepatocyte targeting.

28. The composition of any one of embodiments 1-27, wherein theoligonucleotide comprises a small interfering RNA (siRNA) comprising asense strand and an antisense strand.

29. The composition of embodiment 28, wherein the sense strand is 14-30nucleosides in length.

30. The composition of embodiment 28 or 29, wherein the antisense strandis 14-30 nucleosides in length.

31. A composition comprising an oligonucleotide that inhibits theexpression of ANGPTL4, wherein the oligonucleotide comprises an siRNAcomprising a sense strand and an antisense strand, each strand isindependently about 14-30 nucleosides in length, and at least one of thesense strand and the antisense strand comprises a nucleoside sequencecomprising about 14-30 contiguous nucleosides of SEQ ID NO: 13935.

32. A composition comprising an oligonucleotide that inhibits theexpression of ANGPTL4, wherein the oligonucleotide comprises an siRNAcomprising a sense strand and an antisense strand, each strand isindependently about 14-30 nucleosides in length, and at least one of thesense strand and the antisense strand comprises a nucleoside sequencecomprising about 14-30 contiguous nucleosides of SEQ ID NO: 13936.

33. The composition of any one of embodiments 28-32, wherein the sensestrand and the antisense strand form a double-stranded RNA duplex.

34. The composition of embodiment 33, wherein the first base pair of thedouble-stranded RNA duplex is an AU base pair.

35. The composition of any one of embodiments 28-34, wherein the sensestrand comprises a 3′ overhang comprising 1, 2, or more nucleosides.

36. The composition of embodiment 35, wherein the 3′ overhang of thesense strand comprises 2 nucleosides.

37. The composition of any one of embodiments 28-36, wherein theantisense strand comprises a 3′ overhang comprising 1, 2, or morenucleosides.

38. The composition of embodiment 37, wherein the 3′ overhang of theantisense strand comprises 2 nucleosides.

39. The composition of any one of embodiments 28-38, wherein the sensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleicacid sequence thereof having 1 or 2 nucleoside substitutions, additions,or deletions.

40. The composition of any one of embodiments 28-39, wherein the sensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977.

41. The composition of any one of embodiments 28-40, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions.

42. The composition of any one of embodiments 28-41, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985.

43. The composition of any one of embodiments 28-42, wherein the siRNAbinds with a 17mer in a non-human primate ANGPTL4 mRNA.

44. The composition of any one of embodiments 28-43, wherein the siRNAbinds with a 19mer in a human ANGPTL4 mRNA.

45. The composition of any one of embodiments 28-44, wherein the siRNAbinds with a human ANGPTL4 mRNA and less than or equal to 20 humanoff-targets, with no more than 2 mismatches in the antisense strand.

46. The composition of any one of embodiments 28-45, wherein the siRNAbinds with a human ANGPTL4 mRNA target site that does not harbor an SNP,with a minor allele frequency (MAF) greater or equal to 1% (pos. 2-18).

47. The composition of any one of embodiments 28-46, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 32,33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 84, 111, 112,116, 117, 118, 119, 120, 121, 125, 126, 127, 128, 129, 149, 150, 152,153, 154, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174,175, 177, 196, 198, 199, 210, 211, 212, 214, 215, 216, 217, 218, 219,221, 222, 223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254,255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290,291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332,333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377,380, 382, 386, 388, 391, 392, 393, 394, 397, 398, 399, 402, 404, 405,411, 412, 413, 414, 415, 417, 419, 420, 421, 422, 423, 424, 425, 426,427, 428, 429, 430, 431, 435, 481, 484, 506, 509, 517, 519, 520, 565,570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635,637, 640, 643, 653, 672, 673, 674, 675, 676, 677, 678, 679, 681, 682,683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850,851, 852, 853, 854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888,890, 892, 893, 894, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916,917, 918, 919, 920, 921, 922, 925, 945, 968, 1001, 1002, 1005, 1006,1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054, 1055, 1057,1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147,1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1163, 1164,1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253,1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351,1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430,1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538, 1556, 1561,1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597, 1598, 1601,1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613, 1614, 1617, 1693, 1699,1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751,1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802,or 1803, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions; and wherein the antisense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 1886, 1887,1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933,1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980,1981, 1982, 1983, 2003, 2004, 2006, 2007, 2008, 2011, 2012, 2013, 2015,2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052,2053, 2064, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075, 2076,2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107, 2108,2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134, 2136,2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182,2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201,2203, 2204, 2206, 2207, 2210, 2231, 2234, 2236, 2240, 2242, 2245, 2246,2247, 2248, 2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267, 2268,2269, 2271, 2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282,2283, 2284, 2285, 2289, 2335, 2338, 2360, 2363, 2371, 2373, 2374, 2419,2424, 2425, 2426, 2443, 2461, 2462, 2464, 2465, 2466, 2470, 2471, 2474,2477, 2489, 2491, 2494, 2497, 2507, 2526, 2527, 2528, 2529, 2530, 2531,2532, 2533, 2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546, 2549, 2684,2688, 2695, 2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710, 2711,2713, 2720, 2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746, 2747, 2748,2751, 2754, 2756, 2761, 2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772,2773, 2774, 2775, 2776, 2779, 2799, 2822, 2855, 2856, 2859, 2860, 2863,2864, 2865, 2867, 2882, 2886, 2891, 2906, 2907, 2908, 2909, 2911, 2912,2918, 2966, 2976, 2978, 2980, 2981, 2987, 2988, 2990, 2991, 3001, 3002,3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019,3020, 3025, 3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106, 3107, 3113,3130, 3139, 3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206,3232, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302,3331, 3341, 3342, 3343, 3347, 3348, 3373, 3377, 3392, 3410, 3415, 3417,3418, 3419, 3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456,3457, 3458, 3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 3553, 3555,3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608,3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656, or3657, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions.

48. The composition of any one of embodiments 28-47, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 32,33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 84, 111, 112,116, 117, 118, 119, 120, 121, 125, 126, 127, 128, 129, 149, 150, 152,153, 154, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174,175, 177, 196, 198, 199, 210, 211, 212, 214, 215, 216, 217, 218, 219,221, 222, 223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254,255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290,291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332,333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377,380, 382, 386, 388, 391, 392, 393, 394, 397, 398, 399, 402, 404, 405,411, 412, 413, 414, 415, 417, 419, 420, 421, 422, 423, 424, 425, 426,427, 428, 429, 430, 431, 435, 481, 484, 506, 509, 517, 519, 520, 565,570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635,637, 640, 643, 653, 672, 673, 674, 675, 676, 677, 678, 679, 681, 682,683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850,851, 852, 853, 854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888,890, 892, 893, 894, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916,917, 918, 919, 920, 921, 922, 925, 945, 968, 1001, 1002, 1005, 1006,1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054, 1055, 1057,1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147,1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1163, 1164,1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253,1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351,1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430,1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538, 1556, 1561,1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597, 1598, 1601,1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613, 1614, 1617, 1693, 1699,1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751,1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802,or 1803; and wherein the antisense strand comprises the nucleosidesequence of any one of SEQ ID NOs: 1886, 1887, 1888, 1889, 1890, 1910,1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1938, 1965, 1966,1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982, 1983, 2003,2004, 2006, 2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021,2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066,2068, 2069, 2070, 2071, 2072, 2073, 2075, 2076, 2077, 2082, 2084, 2085,2094, 2095, 2099, 2100, 2104, 2106, 2107, 2108, 2109, 2114, 2115, 2116,2117, 2119, 2120, 2125, 2126, 2128, 2134, 2136, 2143, 2144, 2145, 2146,2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186,2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2204, 2206, 2207,2210, 2231, 2234, 2236, 2240, 2242, 2245, 2246, 2247, 2248, 2251, 2252,2253, 2256, 2258, 2259, 2265, 2266, 2267, 2268, 2269, 2271, 2273, 2274,2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285, 2289,2335, 2338, 2360, 2363, 2371, 2373, 2374, 2419, 2424, 2425, 2426, 2443,2461, 2462, 2464, 2465, 2466, 2470, 2471, 2474, 2477, 2489, 2491, 2494,2497, 2507, 2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533, 2535, 2536,2537, 2538, 2540, 2541, 2543, 2546, 2549, 2684, 2688, 2695, 2696, 2697,2698, 2704, 2705, 2706, 2707, 2708, 2710, 2711, 2713, 2720, 2722, 2725,2726, 2730, 2741, 2742, 2744, 2746, 2747, 2748, 2751, 2754, 2756, 2761,2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774, 2775, 2776,2779, 2799, 2822, 2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882,2886, 2891, 2906, 2907, 2908, 2909, 2911, 2912, 2918, 2966, 2976, 2978,2980, 2981, 2987, 2988, 2990, 2991, 3001, 3002, 3003, 3005, 3007, 3008,3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029,3035, 3036, 3038, 3102, 3103, 3106, 3107, 3113, 3130, 3139, 3164, 3169,3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267,3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341, 3342, 3343,3347, 3348, 3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425,3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458, 3459, 3460,3464, 3465, 3467, 3468, 3471, 3547, 3553, 3555, 3556, 3557, 3576, 3594,3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638,3641, 3642, 3652, 3653, 3654, 3655, 3656, or 3657.

49. The composition of any one of embodiments 28-48, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 33,34, 35, 36, 56, 121, 272, 280, 282, 289, 290, 291, 292, 293, 321, 323,326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347,349, 411, 412, 430, 431, 435, 481, 484, 509, 517, 519, 520, 565, 620,635, 637, 640, 830, 834, 841, 842, 843, 844, 850, 871, 872, 876, 887,888, 894, 897, 902, 945, 1001, 1002, 1005, 1037, 1133, 1134, 1137, 1149,1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1171,1172, 1248, 1249, 1315, 1338, 1343, 1347, 1348, 1429, 1430, 1570, 1571,1572, 1610, 1611, 1617, 1780, 1784, or 1787; and wherein the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 1887,1888, 1889, 1890, 1910, 1975, 2126, 2134, 2136, 2143, 2144, 2145, 2146,2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189,2191, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2335,2338, 2363, 2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494, 2684, 2688,2695, 2696, 2697, 2698, 2704, 2725, 2726, 2730, 2741, 2742, 2748, 2751,2756, 2799, 2855, 2856, 2859, 2891, 2987, 2988, 2991, 3003, 3005, 3007,3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020, 3025, 3026, 3102,3103, 3169, 3192, 3197, 3201, 3202, 3283, 3284, 3424, 3425, 3426, 3464,3465, 3471, 3634, 3638, or 3641.

50. The composition of any one of embodiments 28-49, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 32,33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 112, 116, 117,118, 119, 120, 125, 126, 127, 128, 129, 149, 150, 152, 153, 157, 158,159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 196, 199, 211,212, 214, 215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240,241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266,271, 272, 274, 280, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325,326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347,349, 350, 352, 353, 356, 380, 382, 386, 388, 391, 392, 393, 394, 397,398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 420, 421, 422, 423,424, 425, 426, 427, 428, 429, 430, 431, 435, 484, 517, 519, 520, 565,570, 571, 572, 607, 608, 610, 611, 612, 616, 617, 620, 635, 637, 640,672, 673, 674, 675, 676, 677, 678, 679, 681, 682, 683, 684, 686, 687,689, 692, 695, 830, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856,857, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 902, 911,912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 945, 1001, 1002,1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1052, 1053, 1054, 1055,1057, 1058, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1147, 1148, 1149,1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1175,1182, 1184, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1343, 1347, 1348,1349, 1350, 1351, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429,1430, 1448, 1519, 1523, 1556, 1561, 1563, 1564, 1565, 1571, 1572, 1580,1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1611, 1613, 1614,1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748,1749, 1751, 1754, 1755, 1779, 1780, 1784, 1788, 1798, 1799, 1801, 1802,or 1803; and wherein the antisense strand comprises the nucleosidesequence of any one of SEQ ID NOs: 1886, 1887, 1888, 1889, 1890, 1910,1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1966, 1970, 1971,1972, 1973, 1974, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007,2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028,2029, 2050, 2053, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075,2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107,2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134,2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182,2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201,2203, 2204, 2206, 2207, 2210, 2234, 2236, 2240, 2242, 2245, 2246, 2247,2248, 2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267, 2268, 2269,2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285,2289, 2338, 2371, 2373, 2374, 2419, 2424, 2425, 2426, 2461, 2462, 2464,2465, 2466, 2470, 2471, 2474, 2489, 2491, 2494, 2526, 2527, 2528, 2529,2530, 2531, 2532, 2533, 2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546,2549, 2684, 2695, 2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710,2711, 2720, 2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746, 2747, 2748,2756, 2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774, 2775,2776, 2799, 2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882, 2886,2906, 2907, 2908, 2909, 2911, 2912, 2966, 2976, 2978, 2980, 2981, 2987,2988, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016,3018, 3019, 3020, 3029, 3036, 3038, 3106, 3107, 3113, 3130, 3139, 3164,3169, 3197, 3201, 3202, 3203, 3204, 3205, 3259, 3261, 3267, 3268, 3269,3270, 3271, 3272, 3283, 3284, 3302, 3373, 3377, 3410, 3415, 3417, 3418,3419, 3425, 3426, 3434, 3435, 3443, 3451, 3455, 3456, 3457, 3458, 3459,3460, 3465, 3467, 3468, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595,3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3642,3652, 3653, 3655, 3656, or 3657.

51. The composition of any one of embodiments 28-50, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 33,34, 35, 36, 56, 272, 280, 289, 290, 291, 292, 293, 321, 323, 326, 328,329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 411,412, 430, 431, 435, 484, 517, 519, 520, 565, 620, 635, 637, 640, 830,841, 842, 843, 844, 850, 871, 872, 876, 887, 888, 894, 902, 945, 1001,1002, 1005, 1133, 1134, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161,1162, 1164, 1165, 1166, 1315, 1343, 1347, 1348, 1429, 1430, 1571, 1572,1611, 1780, or 1784; and wherein the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1887, 1888, 1889, 1890,1910, 2126, 2134, 2143, 2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182,2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201,2203, 2265, 2266, 2284, 2285, 2289, 2338, 2371, 2373, 2374, 2419, 2474,2489, 2491, 2494, 2684, 2695, 2696, 2697, 2698, 2704, 2725, 2726, 2730,2741, 2742, 2748, 2756, 2799, 2855, 2856, 2859, 2987, 2988, 3003, 3005,3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020, 3169, 3197,3201, 3202, 3283, 3284, 3425, 3426, 3465, 3634, or 3638.

52. The composition of any one of embodiments 28-51, wherein theantisense strand comprises a seed region that is not identical to a seedregion of a human miRNA.

53. The composition of any one of embodiments 28-52, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 32,36, 56, 57, 58, 61, 62, 79, 80, 117, 119, 125, 126, 128, 149, 152, 157,158, 159, 161, 165, 166, 167, 168, 169, 174, 196, 211, 212, 217, 218,219, 230, 231, 245, 246, 253, 260, 261, 262, 271, 272, 280, 289, 291,292, 293, 304, 321, 323, 325, 326, 328, 330, 331, 332, 333, 334, 337,338, 342, 347, 349, 352, 353, 356, 380, 382, 386, 388, 391, 392, 394,399, 413, 414, 415, 422, 423, 424, 425, 426, 435, 517, 519, 520, 565,571, 607, 608, 612, 617, 620, 635, 640, 672, 673, 674, 675, 678, 679,681, 683, 684, 687, 692, 842, 843, 850, 851, 854, 866, 868, 876, 892,893, 902, 911, 912, 913, 914, 916, 919, 945, 1001, 1002, 1006, 1010,1028, 1052, 1053, 1054, 1055, 1057, 1112, 1124, 1127, 1147, 1149, 1151,1153, 1155, 1157, 1164, 1175, 1182, 1184, 1259, 1276, 1285, 1315, 1343,1349, 1350, 1351, 1405, 1407, 1413, 1415, 1418, 1564, 1571, 1581, 1589,1597, 1601, 1602, 1603, 1604, 1605, 1606, 1613, 1614, 1693, 1701, 1722,1740, 1745, 1751, 1755, 1801, 1802, or 1803, or 3638; and wherein theantisense strand comprises the nucleoside sequence of any one of SEQ IDNOs: 1886, 1890, 1910, 1911, 1912, 1915, 1916, 1933, 1934, 1971, 1973,1979, 1980, 1982, 2003, 2006, 2011, 2012, 2013, 2015, 2019, 2020, 2021,2022, 2023, 2028, 2050, 2065, 2066, 2071, 2072, 2073, 2084, 2085, 2099,2100, 2107, 2114, 2115, 2116, 2125, 2126, 2134, 2143, 2145, 2146, 2147,2158, 2175, 2177, 2179, 2180, 2182, 2184, 2185, 2186, 2187, 2188, 2191,2192, 2196, 2201, 2203, 2206, 2207, 2210, 2234, 2236, 2240, 2242, 2245,2246, 2248, 2253, 2267, 2268, 2269, 2276, 2277, 2278, 2279, 2280, 2289,2371, 2373, 2374, 2419, 2425, 2461, 2462, 2466, 2471, 2474, 2489, 2494,2526, 2527, 2528, 2529, 2532, 2533, 2535, 2537, 2538, 2541, 2546, 2696,2697, 2704, 2705, 2708, 2720, 2722, 2730, 2746, 2747, 2756, 2765, 2766,2767, 2768, 2770, 2773, 2799, 2855, 2856, 2860, 2864, 2882, 2906, 2907,2908, 2909, 2911, 2966, 2978, 2981, 3001, 3003, 3005, 3007, 3009, 3011,3018, 3029, 3036, 3038, 3113, 3130, 3139, 3169, 3197, 3203, 3204, 3205,3259, 3261, 3267, 3269, 3272, 3418, 3425, 3435, 3443, 3451, 3455, 3456,3457, 3458, 3459, 3460, 3467, 3468, 3547, 3555, 3576, 3594, 3599, 3605,3609, 3655, 3656, or 3657.

54. The composition of any one of embodiments 28-53, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID 36, 56,272, 280, 289, 291, 292, 293, 321, 323, 326, 328, 330, 331, 332, 333,334, 337, 338, 342, 347, 349, 435, 517, 519, 520, 565, 620, 635, 640,842, 843, 850, 876, 902, 945, 1001, 1002, 1149, 1151, 1153, 1155, 1157,1164, 1315, 1343, or 1571; and wherein the antisense strand comprisesthe nucleoside sequence of any one of SEQ ID 1890, 1910, 2126, 2134,2143, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2184, 2185, 2186, 2187,2188, 2191, 2192, 2196, 2201, 2203, 2289, 2371, 2373, 2374, 2419, 2474,2489, 2494, 2696, 2697, 2704, 2730, 2756, 2799, 2855, 2856, 3003, 3005,3007, 3009, 3011, 3018, 3169, 3197, or 3425.

55. The composition of any one of embodiments 28-54, wherein the sensestrand comprises a seed region that is not identical to a seed region ofa human miRNA.

56. The composition of any one of embodiments 28-55, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 32,36, 56, 58, 61, 62, 80, 117, 119, 126, 152, 154, 157, 158, 159, 161,166, 169, 174, 177, 196, 211, 212, 217, 218, 230, 231, 245, 253, 260,261, 271, 272, 280, 289, 293, 304, 328, 330, 331, 332, 333, 334, 337,342, 347, 349, 353, 356, 386, 388, 391, 392, 394, 414, 415, 422, 423,424, 426, 435, 520, 571, 608, 612, 617, 653, 672, 678, 679, 681, 683,692, 842, 843, 851, 854, 859, 876, 892, 900, 913, 914, 919, 968, 1001,1002, 1054, 1057, 1064, 1112, 1124, 1157, 1164, 1182, 1184, 1248, 1259,1343, 1351, 1352, 1415, 1418, 1564, 1581, 1602, 1614, 1693, 1701, 1722,1740, 1751, 1755, or 1787; and wherein the antisense strand comprisesthe nucleoside sequence of any one of SEQ ID NOs: 1886, 1890, 1910,1912, 1915, 1916, 1934, 1971, 1973, 1980, 2006, 2008, 2011, 2012, 2013,2015, 2020, 2023, 2028, 2031, 2050, 2065, 2066, 2071, 2072, 2084, 2085,2099, 2107, 2114, 2115, 2125, 2126, 2134, 2143, 2147, 2158, 2182, 2184,2185, 2186, 2187, 2188, 2191, 2196, 2201, 2203, 2207, 2210, 2240, 2242,2245, 2246, 2248, 2268, 2269, 2276, 2277, 2278, 2280, 2289, 2374, 2425,2462, 2466, 2471, 2507, 2526, 2532, 2533, 2535, 2537, 2546, 2696, 2697,2705, 2708, 2713, 2730, 2746, 2754, 2767, 2768, 2773, 2822, 2855, 2856,2908, 2911, 2918, 2966, 2978, 3011, 3018, 3036, 3038, 3102, 3113, 3197,3205, 3206, 3269, 3272, 3418, 3435, 3456, 3468, 3547, 3555, 3576, 3594,3605, 3609, or 3641.

57. The composition of any one of embodiments 28-56, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOs: 36,56, 272, 280, 289, 293, 328, 330, 331, 332, 333, 334, 337, 342, 347,349, 435, 520, 842, 843, 876, 1001, 1002, 1157, 1164, or 1343; andwherein the antisense strand comprises the nucleoside sequence of anyone of SEQ ID NOs: 1890, 1910, 2126, 2134, 2143, 2147, 2182, 2184, 2185,2186, 2187, 2188, 2191, 2196, 2201, 2203, 2289, 2374, 2696, 2697, 2730,2855, 2856, 3011, 3018, or 3197.

58. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 1S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

59. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 2S:5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

60. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 3S:5′-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′ fluoro-modifiednucleoside, “n” is a 2′ O-methyl modified nucleoside, and “s” is aphosphorothioate linkage.

61. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 4S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,“s” is a phosphorothioate linkage, and N comprises one or morenucleosides.

62. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 5S:5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,“s” is a phosphorothioate linkage, and N comprises one or morenucleosides.

63. The composition of any one of embodiments 28-62, wherein theantisense strand comprises modification pattern 1AS:5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

64. The composition of any one of embodiments 28-62, wherein theantisense strand comprises modification pattern 2AS:5′-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

65. The composition of any one of embodiments 28-62, wherein theantisense strand comprises modification pattern 3AS:5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

66. The composition of any one of embodiments 28-62, wherein theantisense strand comprises modification pattern 4AS:5′-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

67. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 1S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, or 4AS.

68. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 2S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, or 4AS.

69. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 3S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, or 4AS.

70. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 4S and the antisense strandcomprises modification pattern 1AS, 2AS, 3AS, or 4AS.

71. The composition of any one of embodiments 28-57, wherein the sensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, a nucleic acidsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions, and modification pattern 1S.

72. The composition of any one of embodiments 28-57, wherein the sensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, andmodification pattern 1S.

73. The composition of any one of embodiments 28-57, wherein the sensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleicacid sequence thereof having 1 or 2 nucleoside substitutions, additions,or deletions, and modification pattern 2S.

74. The composition of any one of embodiments 28-57, wherein the sensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, andmodification pattern 2S.

75. The composition of any one of embodiments 28-57 or 71-74, whereinthe antisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 1AS.

76. The composition of any one of embodiments 28-57 or 71-74, whereinthe antisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, and modification pattern 1AS.

77. The composition of any one of embodiments 28-57 or 71-74, whereinthe antisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 3AS.

78. The composition of any one of embodiments 28-57 or 71-74, whereinthe antisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, and modification pattern 3AS.

79. The composition of any one of embodiments 1-27, wherein theoligonucleotide comprises an antisense oligonucleotide (ASO).

80. The composition of embodiment 79, wherein the ASO is 12-30nucleosides in length.

81. A composition comprising an oligonucleotide that inhibits theexpression of ANGPTL4, wherein the oligonucleotide comprises an ASOabout 12-30 nucleosides in length and comprising a nucleoside sequencecomplementary to about 12-30 contiguous nucleosides of SEQ ID NO: 13935.

82. A composition comprising an oligonucleotide that inhibits theexpression of ANGPTL4, wherein the oligonucleotide comprises an ASOabout 12-30 nucleosides in length and comprising a nucleoside sequencecomplementary to about 12-30 contiguous nucleosides of SEQ ID NO: 13936.

83. The composition of any one of embodiments 79-82, wherein the ASO is15-25 nucleosides in length.

84. The composition of any one of embodiments 79-83, wherein the ASO is20 nucleosides in length.

85. The composition of any one of embodiments 79-84, wherein the ASOcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 3709-13934, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions.

86. The composition of any one of embodiments 79-85, wherein the ASOcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 3709-13934.

87. The composition of any one of embodiments 79-86, wherein the ASOcomprises modification pattern:5′-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3′ where “dN” isany deoxynucleotide, “n” is a 2′O-methyl or 2′O-methoxyethyl-modifiednucleoside, and “s” is a phosphorothioate linkage.

88. The composition of any one of embodiments 79-86, wherein the ASOcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 3709-13934, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions, andmodification pattern ASO1.

89. The composition of any one of embodiments 79-86, wherein the ASOcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 3709-13934, and modification pattern ASO1.

90. The composition of any one of embodiments 1-89, wherein thecomposition is a pharmaceutical composition.

91. The composition of any one of embodiments 1-90, wherein thecomposition is sterile. 92. The composition of any one of embodiments1-91, further comprising a pharmaceutically acceptable carrier.

93. The composition of embodiment 92, wherein the pharmaceuticallyacceptable carrier comprises water, a buffer, or a saline solution.

94. Use of a composition comprising an oligonucleotide that targetsANGPTL4 in a method of treating a metabolic disorder in a subject inneed thereof, the method comprising administering to the subject thecomposition.

95. The use of embodiment 94, wherein the metabolic disorder compriseshyperlipidemia.

96. The use of embodiment 94, wherein the metabolic disorder compriseshypertriglyceridemia.

97. The use of embodiment 94, wherein the metabolic disorder comprisesdiabetes.

98. The use of embodiment 94, wherein the metabolic disorder comprisestype 2 diabetes.

99. Use of a composition comprising an oligonucleotide that targetsANGPTL4 in a method of treating a cardiovascular disorder in a subjectin need thereof, the method comprising administering to the subject thecomposition.

100. The use of embodiment 99, wherein the cardiovascular disordercomprises heart disease.

101. The use of embodiment 99, wherein the cardiovascular disordercomprises myocardial infarction.

102. The use of embodiment 99, wherein the cardiovascular disordercomprises angina pectoris.

103. The use of embodiment 99, wherein the cardiovascular disordercomprises atherosclerosis.

104. The use of any one of embodiments 94-103, wherein the subject is ananimal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, aprimate, or a monkey.

105. The use of any one of embodiments 94-104, wherein the subject is ahuman.

106. The use of any one of embodiments 94-105, wherein the subject is≥40 years of age.

107. The use of any one of embodiments 94-105, wherein the subject is≤85 years of age.

108. The use of any one of embodiments 94-105, wherein the subject is≥40 and ≤85 years of age.

109. The use of any one of embodiments 94-109, wherein a baselinemeasurement is obtained in a sample obtained from the subject prior toadministering the composition to the subject.

110. The use of embodiment 109, wherein the sample is obtained from thesubject after an overnight fasting period.

111. The use of embodiment 109, wherein the sample is obtained from thesubject in a fed state.

112. The use of one of embodiments 109-111, wherein the baselinemeasurement is obtained by an immunoassay, a colorimetric assay, or afluorescence assay.

113. The use of any one of embodiments 109-112, wherein the sample is ablood, plasma, or serum sample.

114. The use of one of embodiments 109-113, wherein the sample is aserum sample. 115. The use of any one of embodiments 109-114, whereinthe baseline measurement is a baseline triglyceride measurement.

116. The use of any one of embodiments 109-114, wherein the baselinemeasurement is a baseline cholesterol measurement.

117. The use of any one of embodiments 109-114, wherein the baselinemeasurement is a baseline HDL measurement.

118. The use of any one of embodiments 109-114, wherein the baselinemeasurement is a baseline glucose measurement.

119. The use of any one of embodiments 109-114, wherein the baselinemeasurement is a baseline insulin sensitivity measurement.

120. The use of any one of embodiments 109-112, wherein the sample is atissue sample.

121. The use of embodiment 120, wherein the tissue sample comprisesliver, adipose, small intestine, mesenteric lymph node, or cardiactissue.

122. The use of embodiment 120 or 121, wherein the tissue sample is aliver sample.

123. The use of any one of embodiments 109-122, wherein the baselinemeasurement is a baseline ANGPTL4 protein measurement.

124. The use of any one of embodiments 109-122, wherein the baselinemeasurement is a baseline ANGPTL4 mRNA measurement.

125. The use of embodiment 124, wherein the baseline measurement isobtained by PCR.

126. The use of embodiment 115, wherein the composition reducescirculating triglycerides relative to the baseline triglyceridemeasurement.

127. The use of embodiment 126, wherein the reduced triglycerides aremeasured in a second sample obtained from the subject afteradministering the composition to the subject.

128. The use of embodiment 116, wherein the composition reducescirculating cholesterol relative to the baseline cholesterolmeasurement.

129. The use of embodiment 128, wherein the reduced cholesterol ismeasured in a second sample obtained from the subject afteradministering the composition to the subject.

130. The use of embodiment 117, wherein the composition increasescirculating HDL relative to the baseline HDL measurement.

131. The use of embodiment 130, wherein the increased HDL is measured ina second sample obtained from the subject after administering thecomposition to the subject.

132. The use of embodiment 118, wherein the composition reducescirculating glucose relative to the baseline glucose measurement.

133. The use of embodiment 132, wherein the reduced glucose is measuredin a second sample obtained from the subject after administering thecomposition to the subject.

134. The use of embodiment 119, wherein the composition improves insulinsensitivity relative to the baseline insulin sensitivity measurement.

135. The use of embodiment 134, wherein the improves insulin sensitivityis measured in a second sample obtained from the subject afteradministering the composition to the subject.

136. The use of embodiment 123, wherein the composition reducescirculating ANGPTL4 protein levels relative to the baseline ANGPTL4protein measurement.

137. The use of embodiment 136, wherein the reduced ANGPTL4 proteinlevels are measured in a second sample obtained from the subject afteradministering the composition to the subject.

138. The use of embodiment 124 or 125, wherein the composition reducesANGPTL4 mRNA levels relative to the baseline ANGPTL4 mRNA measurement.

139. The use of embodiment 138, wherein the reduced ANGPTL4 mRNA levelsare measured in a second sample obtained from the subject afteradministering the composition to the subject.

140. The use of any one of embodiments 94-139, wherein theoligonucleotide comprises a modified internucleoside linkage.

141. The use of embodiment 140, wherein the modified internucleosidelinkage comprises alkylphosphonate, phosphorothioate, methylphosphonate,phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate,carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or acombination thereof.

142. The use of embodiment 140, wherein the modified internucleosidelinkage comprises one or more phosphorothioate linkages.

143. The use of any one of embodiments 94-142, wherein theoligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20 modified internucleoside linkages.

144. The use of any one of embodiments 94-143, wherein theoligonucleotide comprises 2 or more modified internucleoside linkages, 3or more modified internucleoside linkages, 4 or more modifiedinternucleoside linkages, 5 or more modified internucleoside linkages, 6or more modified internucleoside linkages, 7 or more modifiedinternucleoside linkages, 8 or more modified internucleoside linkages, 9or more modified internucleoside linkages, 10 or more modifiedinternucleoside linkages, 11 or more modified internucleoside linkages,12 or more modified internucleoside linkages, 13 or more modifiedinternucleoside linkages, 14 or more modified internucleoside linkages,15 or more modified internucleoside linkages, 16 or more modifiedinternucleoside linkages, 17 or more modified internucleoside linkages,18 or more modified internucleoside linkages, 19 or more modifiedinternucleoside linkages, or 20 or more modified internucleosidelinkages.

145. The use of any one of embodiments 94-144, wherein theoligonucleotide comprises a modified nucleoside.

146. The use of embodiment 145, wherein the modified nucleosidecomprises a locked nucleic acid (LNA), hexitol nucleic acid (HLA),cyclohexene nucleic acid (CeNA), 2′-methoxyethyl, 2′-O-alkyl,2′-O-allyl, 2′-O-allyl, 2′-fluoro, or 2′-deoxy, or a combinationthereof.

147. The use of embodiment 145, wherein the modified nucleosidecomprises a LNA.

148. The use of embodiment 145, wherein the modified nucleosidecomprises a 2′,4′ constrained ethyl nucleic acid.

149. The use of embodiment 145, wherein the modified nucleosidecomprises a 2′-O-methyl nucleoside, 2′-deoxyfluoro nucleoside,2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl(2′-O-AP) nucleoside, or 2′-ara-F, or a combination thereof.

150. The use of embodiment 145, wherein the modified nucleosidecomprises one or more 2′fluoro modified nucleosides.

151. The use of embodiment 145, wherein the modified nucleosidecomprises a 2′ O-alkyl modified nucleoside.

152. The use of embodiment 145, wherein the oligonucleotide comprises alipid attached at a 3′ or 5′ terminus of the oligonucleotide.

153. The use of embodiment 152, wherein the lipid comprises cholesterol,myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl,docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or acombination thereof.

154. The use of any one of embodiments 94-153, wherein theoligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, or 21 modified nucleosides.

155. The use of any one of embodiments 94-154, wherein theoligonucleotide comprises 2 or more modified nucleosides, 3 or moremodified nucleosides, 4 or more modified nucleosides, 5 or more modifiednucleosides, 6 or more modified nucleosides, 7 or more modifiednucleosides, 8 or more modified nucleosides, 9 or more modifiednucleosides, 10 or more modified nucleosides, 11 or more modifiednucleosides, 12 or more modified nucleosides, 13 or more modifiednucleosides, 14 or more modified nucleosides, 15 or more modifiednucleosides, 16 or more modified nucleosides, 17 or more modifiednucleosides, 18 or more modified nucleosides, 19 or more modifiednucleosides, 20 or more modified nucleosides, or 21 or more modifiednucleosides.

156. The use of any one of embodiments 94-155, wherein theoligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand forhepatocyte targeting.

157. The use of any one of embodiments 94-156, wherein theoligonucleotide comprises an siRNA comprising a sense strand and anantisense strand.

158. The use of embodiment 157, wherein the sense strand is 14-30nucleosides in length.

159. The use of embodiment 157 or 158, wherein the antisense strand is14-30 nucleosides in length.

160. The use of any one of embodiments 94-156, wherein theoligonucleotide comprises an siRNA comprising a sense strand and anantisense strand, each strand is independently about 14-30 nucleosidesin length, and at least one of the sense strand and the antisense strandcomprises a nucleoside sequence comprising about 14-30 contiguousnucleosides of SEQ ID NO: 13935.

161. The use of any one of embodiments 94-156, wherein theoligonucleotide comprises an siRNA comprising a sense strand and anantisense strand, each strand is independently about 14-30 nucleosidesin length, and at least one of the sense strand and the antisense strandcomprises a nucleoside sequence comprising about 14-30 contiguousnucleosides of SEQ ID NO: 13936.

162. The use of any one of embodiments 157-161, wherein the sense strandand the antisense strand form a double-stranded RNA duplex.

163. The use of embodiment 162, wherein the first base pair of thedouble-stranded RNA duplex is an AU base pair.

164. The use of any one of embodiments 157-163, wherein the sense strandcomprises a 3′ overhang comprising 1, 2, or more nucleosides.

165. The use of embodiment 164, wherein the 3′ overhang of the sensestrand comprises 2 nucleosides.

166. The use of any one of embodiments 157-165, wherein the antisensestrand comprises a 3′ overhang comprising 1, 2, or more nucleosides.

167. The use of embodiment 166, wherein the 3′ overhang of the antisensestrand comprises 2 nucleosides.

168. The use of any one of embodiments 157-167, wherein the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acidsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions.

169. The use of any one of embodiments 157-168, wherein the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977.

170. The use of any one of embodiments 157-169, wherein the antisensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions.

171. The use of any one of embodiments 157-170, wherein the antisensestrand comprises a nucleoside sequence comprising or consisting of thesequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985.

172. The use of any one of embodiments 157-171, wherein the siRNA bindswith a 17mer in a non-human primate ANGPTL4 mRNA.

173. The use of any one of embodiments 157-172, wherein the siRNA bindswith a 19mer in a human ANGPTL4 mRNA.

174. The use of any one of embodiments 157-173, wherein the siRNA bindswith a human ANGPTL4 mRNA and less than or equal to 20 humanoff-targets, with no more than 2 mismatches in the antisense strand.

175. The use of any one of embodiments 157-174, wherein the siRNA bindswith a human ANGPTL4 mRNA target site that does not harbor an SNP, witha minor allele frequency (MAF) greater or equal to 1% (pos. 2-18).

176. The use of any one of embodiments 157-175, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 32, 33, 34,35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 84, 111, 112, 116, 117,118, 119, 120, 121, 125, 126, 127, 128, 129, 149, 150, 152, 153, 154,157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 177,196, 198, 199, 210, 211, 212, 214, 215, 216, 217, 218, 219, 221, 222,223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260,261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290, 291, 292,293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334,335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377, 380, 382,386, 388, 391, 392, 393, 394, 397, 398, 399, 402, 404, 405, 411, 412,413, 414, 415, 417, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428,429, 430, 431, 435, 481, 484, 506, 509, 517, 519, 520, 565, 570, 571,572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635, 637, 640,643, 653, 672, 673, 674, 675, 676, 677, 678, 679, 681, 682, 683, 684,686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850, 851, 852,853, 854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888, 890, 892,893, 894, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916, 917, 918,919, 920, 921, 922, 925, 945, 968, 1001, 1002, 1005, 1006, 1009, 1010,1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054, 1055, 1057, 1058, 1064,1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147, 1148, 1149,1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1163, 1164, 1165, 1166,1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253, 1259, 1276,1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351, 1352, 1378,1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430, 1448, 1477,1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538, 1556, 1561, 1563, 1564,1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597, 1598, 1601, 1602, 1603,1604, 1605, 1606, 1610, 1611, 1613, 1614, 1617, 1693, 1699, 1701, 1702,1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755,1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802, or 1803, ora nucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions; and wherein the antisense strand comprises thenucleoside sequence of any one of SEQ ID NOs: 1886, 1887, 1888, 1889,1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1938,1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982,1983, 2003, 2004, 2006, 2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019,2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064,2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075, 2076, 2077, 2082,2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107, 2108, 2109, 2114,2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134, 2136, 2143, 2144,2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184,2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2204,2206, 2207, 2210, 2231, 2234, 2236, 2240, 2242, 2245, 2246, 2247, 2248,2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267, 2268, 2269, 2271,2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284,2285, 2289, 2335, 2338, 2360, 2363, 2371, 2373, 2374, 2419, 2424, 2425,2426, 2443, 2461, 2462, 2464, 2465, 2466, 2470, 2471, 2474, 2477, 2489,2491, 2494, 2497, 2507, 2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533,2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546, 2549, 2684, 2688, 2695,2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710, 2711, 2713, 2720,2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746, 2747, 2748, 2751, 2754,2756, 2761, 2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774,2775, 2776, 2779, 2799, 2822, 2855, 2856, 2859, 2860, 2863, 2864, 2865,2867, 2882, 2886, 2891, 2906, 2907, 2908, 2909, 2911, 2912, 2918, 2966,2976, 2978, 2980, 2981, 2987, 2988, 2990, 2991, 3001, 3002, 3003, 3005,3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025,3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106, 3107, 3113, 3130, 3139,3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259,3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341,3342, 3343, 3347, 3348, 3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419,3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458,3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 3553, 3555, 3556, 3557,3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633,3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656, or 3657, or anucleic acid sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions.

177. The use of any one of embodiments 157-176, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 32, 33, 34,35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 84, 111, 112, 116, 117,118, 119, 120, 121, 125, 126, 127, 128, 129, 149, 150, 152, 153, 154,157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 177,196, 198, 199, 210, 211, 212, 214, 215, 216, 217, 218, 219, 221, 222,223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260,261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290, 291, 292,293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334,335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377, 380, 382,386, 388, 391, 392, 393, 394, 397, 398, 399, 402, 404, 405, 411, 412,413, 414, 415, 417, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428,429, 430, 431, 435, 481, 484, 506, 509, 517, 519, 520, 565, 570, 571,572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635, 637, 640,643, 653, 672, 673, 674, 675, 676, 677, 678, 679, 681, 682, 683, 684,686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850, 851, 852,853, 854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888, 890, 892,893, 894, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916, 917, 918,919, 920, 921, 922, 925, 945, 968, 1001, 1002, 1005, 1006, 1009, 1010,1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054, 1055, 1057, 1058, 1064,1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147, 1148, 1149,1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1163, 1164, 1165, 1166,1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253, 1259, 1276,1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351, 1352, 1378,1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430, 1448, 1477,1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538, 1556, 1561, 1563, 1564,1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597, 1598, 1601, 1602, 1603,1604, 1605, 1606, 1610, 1611, 1613, 1614, 1617, 1693, 1699, 1701, 1702,1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755,1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802, or 1803; andwherein the antisense strand comprises the nucleoside sequence of anyone of SEQ ID NOs: 1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913,1915, 1916, 1917, 1918, 1933, 1934, 1938, 1965, 1966, 1970, 1971, 1972,1973, 1974, 1975, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007,2008, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026,2028, 2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066, 2068, 2069, 2070,2071, 2072, 2073, 2075, 2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099,2100, 2104, 2106, 2107, 2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120,2125, 2126, 2128, 2134, 2136, 2143, 2144, 2145, 2146, 2147, 2153, 2158,2175, 2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189,2191, 2192, 2193, 2196, 2201, 2203, 2204, 2206, 2207, 2210, 2231, 2234,2236, 2240, 2242, 2245, 2246, 2247, 2248, 2251, 2252, 2253, 2256, 2258,2259, 2265, 2266, 2267, 2268, 2269, 2271, 2273, 2274, 2275, 2276, 2277,2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285, 2289, 2335, 2338, 2360,2363, 2371, 2373, 2374, 2419, 2424, 2425, 2426, 2443, 2461, 2462, 2464,2465, 2466, 2470, 2471, 2474, 2477, 2489, 2491, 2494, 2497, 2507, 2526,2527, 2528, 2529, 2530, 2531, 2532, 2533, 2535, 2536, 2537, 2538, 2540,2541, 2543, 2546, 2549, 2684, 2688, 2695, 2696, 2697, 2698, 2704, 2705,2706, 2707, 2708, 2710, 2711, 2713, 2720, 2722, 2725, 2726, 2730, 2741,2742, 2744, 2746, 2747, 2748, 2751, 2754, 2756, 2761, 2765, 2766, 2767,2768, 2769, 2770, 2771, 2772, 2773, 2774, 2775, 2776, 2779, 2799, 2822,2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882, 2886, 2891, 2906,2907, 2908, 2909, 2911, 2912, 2918, 2966, 2976, 2978, 2980, 2981, 2987,2988, 2990, 2991, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012,3015, 3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029, 3035, 3036, 3038,3102, 3103, 3106, 3107, 3113, 3130, 3139, 3164, 3169, 3192, 3197, 3201,3202, 3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267, 3268, 3269, 3270,3271, 3272, 3283, 3284, 3302, 3331, 3341, 3342, 3343, 3347, 3348, 3373,3377, 3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425, 3426, 3434, 3435,3443, 3451, 3452, 3455, 3456, 3457, 3458, 3459, 3460, 3464, 3465, 3467,3468, 3471, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595, 3596, 3599,3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652,3653, 3654, 3655, 3656, or 3657.

178. The use of any one of embodiments 157-177, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 33, 34, 35,36, 56, 121, 272, 280, 282, 289, 290, 291, 292, 293, 321, 323, 326, 328,329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 411,412, 430, 431, 435, 481, 484, 509, 517, 519, 520, 565, 620, 635, 637,640, 830, 834, 841, 842, 843, 844, 850, 871, 872, 876, 887, 888, 894,897, 902, 945, 1001, 1002, 1005, 1037, 1133, 1134, 1137, 1149, 1151,1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1171, 1172,1248, 1249, 1315, 1338, 1343, 1347, 1348, 1429, 1430, 1570, 1571, 1572,1610, 1611, 1617, 1780, 1784, or 1787; and wherein the antisense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 1887, 1888,1889, 1890, 1910, 1975, 2126, 2134, 2136, 2143, 2144, 2145, 2146, 2147,2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191,2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2335, 2338,2363, 2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494, 2684, 2688, 2695,2696, 2697, 2698, 2704, 2725, 2726, 2730, 2741, 2742, 2748, 2751, 2756,2799, 2855, 2856, 2859, 2891, 2987, 2988, 2991, 3003, 3005, 3007, 3008,3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020, 3025, 3026, 3102, 3103,3169, 3192, 3197, 3201, 3202, 3283, 3284, 3424, 3425, 3426, 3464, 3465,3471, 3634, 3638, or 3641.

179. The use of any one of embodiments 157-178, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 32, 33, 34,35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 112, 116, 117, 118, 119,120, 125, 126, 127, 128, 129, 149, 150, 152, 153, 157, 158, 159, 161,164, 165, 166, 167, 168, 169, 172, 174, 175, 196, 199, 211, 212, 214,215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245,246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272,274, 280, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328,329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350,352, 353, 356, 380, 382, 386, 388, 391, 392, 393, 394, 397, 398, 399,402, 404, 405, 411, 412, 413, 414, 415, 420, 421, 422, 423, 424, 425,426, 427, 428, 429, 430, 431, 435, 484, 517, 519, 520, 565, 570, 571,572, 607, 608, 610, 611, 612, 616, 617, 620, 635, 637, 640, 672, 673,674, 675, 676, 677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692,695, 830, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 866,868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 902, 911, 912, 913,914, 915, 916, 917, 918, 919, 920, 921, 922, 945, 1001, 1002, 1005,1006, 1009, 1010, 1011, 1013, 1028, 1032, 1052, 1053, 1054, 1055, 1057,1058, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1147, 1148, 1149, 1151,1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1175, 1182,1184, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1343, 1347, 1348, 1349,1350, 1351, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430,1448, 1519, 1523, 1556, 1561, 1563, 1564, 1565, 1571, 1572, 1580, 1581,1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1611, 1613, 1614, 1693,1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749,1751, 1754, 1755, 1779, 1780, 1784, 1788, 1798, 1799, 1801, 1802, or1803; and wherein the antisense strand comprises the nucleoside sequenceof any one of SEQ ID NOs: 1886, 1887, 1888, 1889, 1890, 1910, 1911,1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1966, 1970, 1971, 1972,1973, 1974, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007, 2011,2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029,2050, 2053, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075, 2076,2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107, 2108,2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134, 2143,2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182, 2183,2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203,2204, 2206, 2207, 2210, 2234, 2236, 2240, 2242, 2245, 2246, 2247, 2248,2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267, 2268, 2269, 2274,2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285, 2289,2338, 2371, 2373, 2374, 2419, 2424, 2425, 2426, 2461, 2462, 2464, 2465,2466, 2470, 2471, 2474, 2489, 2491, 2494, 2526, 2527, 2528, 2529, 2530,2531, 2532, 2533, 2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546, 2549,2684, 2695, 2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710, 2711,2720, 2722, 2725, 2726, 2730, 2741, 2742, 2744, 2746, 2747, 2748, 2756,2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774, 2775, 2776,2799, 2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882, 2886, 2906,2907, 2908, 2909, 2911, 2912, 2966, 2976, 2978, 2980, 2981, 2987, 2988,3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018,3019, 3020, 3029, 3036, 3038, 3106, 3107, 3113, 3130, 3139, 3164, 3169,3197, 3201, 3202, 3203, 3204, 3205, 3259, 3261, 3267, 3268, 3269, 3270,3271, 3272, 3283, 3284, 3302, 3373, 3377, 3410, 3415, 3417, 3418, 3419,3425, 3426, 3434, 3435, 3443, 3451, 3455, 3456, 3457, 3458, 3459, 3460,3465, 3467, 3468, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595, 3596,3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3642, 3652,3653, 3655, 3656, or 3657.

180. The use of any one of embodiments 157-179, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 33, 34, 35,36, 56, 272, 280, 289, 290, 291, 292, 293, 321, 323, 326, 328, 329, 330,331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 411, 412, 430,431, 435, 484, 517, 519, 520, 565, 620, 635, 637, 640, 830, 841, 842,843, 844, 850, 871, 872, 876, 887, 888, 894, 902, 945, 1001, 1002, 1005,1133, 1134, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164,1165, 1166, 1315, 1343, 1347, 1348, 1429, 1430, 1571, 1572, 1611, 1780,or 1784; and wherein the antisense strand comprises the nucleosidesequence of any one of SEQ ID NOs: 1887, 1888, 1889, 1890, 1910, 2126,2134, 2143, 2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184,2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2265,2266, 2284, 2285, 2289, 2338, 2371, 2373, 2374, 2419, 2474, 2489, 2491,2494, 2684, 2695, 2696, 2697, 2698, 2704, 2725, 2726, 2730, 2741, 2742,2748, 2756, 2799, 2855, 2856, 2859, 2987, 2988, 3003, 3005, 3007, 3008,3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020, 3169, 3197, 3201, 3202,3283, 3284, 3425, 3426, 3465, 3634, or 3638.

181. The use of any one of embodiments 157-180, wherein the antisensestrand comprises a seed region that is not identical to a seed region ofa human miRNA.

182. The use of any one of embodiments 157-181, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 32, 36, 56,57, 58, 61, 62, 79, 80, 117, 119, 125, 126, 128, 149, 152, 157, 158,159, 161, 165, 166, 167, 168, 169, 174, 196, 211, 212, 217, 218, 219,230, 231, 245, 246, 253, 260, 261, 262, 271, 272, 280, 289, 291, 292,293, 304, 321, 323, 325, 326, 328, 330, 331, 332, 333, 334, 337, 338,342, 347, 349, 352, 353, 356, 380, 382, 386, 388, 391, 392, 394, 399,413, 414, 415, 422, 423, 424, 425, 426, 435, 517, 519, 520, 565, 571,607, 608, 612, 617, 620, 635, 640, 672, 673, 674, 675, 678, 679, 681,683, 684, 687, 692, 842, 843, 850, 851, 854, 866, 868, 876, 892, 893,902, 911, 912, 913, 914, 916, 919, 945, 1001, 1002, 1006, 1010, 1028,1052, 1053, 1054, 1055, 1057, 1112, 1124, 1127, 1147, 1149, 1151, 1153,1155, 1157, 1164, 1175, 1182, 1184, 1259, 1276, 1285, 1315, 1343, 1349,1350, 1351, 1405, 1407, 1413, 1415, 1418, 1564, 1571, 1581, 1589, 1597,1601, 1602, 1603, 1604, 1605, 1606, 1613, 1614, 1693, 1701, 1722, 1740,1745, 1751, 1755, 1801, 1802, or 1803, or 3638; and wherein theantisense strand comprises the nucleoside sequence of any one of SEQ IDNOs: 1886, 1890, 1910, 1911, 1912, 1915, 1916, 1933, 1934, 1971, 1973,1979, 1980, 1982, 2003, 2006, 2011, 2012, 2013, 2015, 2019, 2020, 2021,2022, 2023, 2028, 2050, 2065, 2066, 2071, 2072, 2073, 2084, 2085, 2099,2100, 2107, 2114, 2115, 2116, 2125, 2126, 2134, 2143, 2145, 2146, 2147,2158, 2175, 2177, 2179, 2180, 2182, 2184, 2185, 2186, 2187, 2188, 2191,2192, 2196, 2201, 2203, 2206, 2207, 2210, 2234, 2236, 2240, 2242, 2245,2246, 2248, 2253, 2267, 2268, 2269, 2276, 2277, 2278, 2279, 2280, 2289,2371, 2373, 2374, 2419, 2425, 2461, 2462, 2466, 2471, 2474, 2489, 2494,2526, 2527, 2528, 2529, 2532, 2533, 2535, 2537, 2538, 2541, 2546, 2696,2697, 2704, 2705, 2708, 2720, 2722, 2730, 2746, 2747, 2756, 2765, 2766,2767, 2768, 2770, 2773, 2799, 2855, 2856, 2860, 2864, 2882, 2906, 2907,2908, 2909, 2911, 2966, 2978, 2981, 3001, 3003, 3005, 3007, 3009, 3011,3018, 3029, 3036, 3038, 3113, 3130, 3139, 3169, 3197, 3203, 3204, 3205,3259, 3261, 3267, 3269, 3272, 3418, 3425, 3435, 3443, 3451, 3455, 3456,3457, 3458, 3459, 3460, 3467, 3468, 3547, 3555, 3576, 3594, 3599, 3605,3609, 3655, 3656, or 3657.

183. The use of any one of embodiments 157-182, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID 36, 56, 272, 280,289, 291, 292, 293, 321, 323, 326, 328, 330, 331, 332, 333, 334, 337,338, 342, 347, 349, 435, 517, 519, 520, 565, 620, 635, 640, 842, 843,850, 876, 902, 945, 1001, 1002, 1149, 1151, 1153, 1155, 1157, 1164,1315, 1343, or 1571; and wherein the antisense strand comprises thenucleoside sequence of any one of SEQ ID 1890, 1910, 2126, 2134, 2143,2145, 2146, 2147, 2175, 2177, 2180, 2182, 2184, 2185, 2186, 2187, 2188,2191, 2192, 2196, 2201, 2203, 2289, 2371, 2373, 2374, 2419, 2474, 2489,2494, 2696, 2697, 2704, 2730, 2756, 2799, 2855, 2856, 3003, 3005, 3007,3009, 3011, 3018, 3169, 3197, or 3425.

184. The use of any one of embodiments 157-183, wherein the sense strandcomprises a seed region that is not identical to a seed region of ahuman miRNA.

185. The use of any one of embodiments 157-184, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 32, 36, 56,58, 61, 62, 80, 117, 119, 126, 152, 154, 157, 158, 159, 161, 166, 169,174, 177, 196, 211, 212, 217, 218, 230, 231, 245, 253, 260, 261, 271,272, 280, 289, 293, 304, 328, 330, 331, 332, 333, 334, 337, 342, 347,349, 353, 356, 386, 388, 391, 392, 394, 414, 415, 422, 423, 424, 426,435, 520, 571, 608, 612, 617, 653, 672, 678, 679, 681, 683, 692, 842,843, 851, 854, 859, 876, 892, 900, 913, 914, 919, 968, 1001, 1002, 1054,1057, 1064, 1112, 1124, 1157, 1164, 1182, 1184, 1248, 1259, 1343, 1351,1352, 1415, 1418, 1564, 1581, 1602, 1614, 1693, 1701, 1722, 1740, 1751,1755, or 1787; and wherein the antisense strand comprises the nucleosidesequence of any one of SEQ ID NOs: 1886, 1890, 1910, 1912, 1915, 1916,1934, 1971, 1973, 1980, 2006, 2008, 2011, 2012, 2013, 2015, 2020, 2023,2028, 2031, 2050, 2065, 2066, 2071, 2072, 2084, 2085, 2099, 2107, 2114,2115, 2125, 2126, 2134, 2143, 2147, 2158, 2182, 2184, 2185, 2186, 2187,2188, 2191, 2196, 2201, 2203, 2207, 2210, 2240, 2242, 2245, 2246, 2248,2268, 2269, 2276, 2277, 2278, 2280, 2289, 2374, 2425, 2462, 2466, 2471,2507, 2526, 2532, 2533, 2535, 2537, 2546, 2696, 2697, 2705, 2708, 2713,2730, 2746, 2754, 2767, 2768, 2773, 2822, 2855, 2856, 2908, 2911, 2918,2966, 2978, 3011, 3018, 3036, 3038, 3102, 3113, 3197, 3205, 3206, 3269,3272, 3418, 3435, 3456, 3468, 3547, 3555, 3576, 3594, 3605, 3609, or3641.

186. The use of any one of embodiments 157-185, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOs: 36, 56, 272,280, 289, 293, 328, 330, 331, 332, 333, 334, 337, 342, 347, 349, 435,520, 842, 843, 876, 1001, 1002, 1157, 1164, or 1343; and wherein theantisense strand comprises the nucleoside sequence of any one of SEQ IDNOs: 1890, 1910, 2126, 2134, 2143, 2147, 2182, 2184, 2185, 2186, 2187,2188, 2191, 2196, 2201, 2203, 2289, 2374, 2696, 2697, 2730, 2855, 2856,3011, 3018, or 3197.

187. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 1S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

188. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′,wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methylmodified nucleoside, and “s” is a phosphorothioate linkage.

189. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 3S: 5′-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′,wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methylmodified nucleoside, and “s” is a phosphorothioate linkage.

190. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 4S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,“s” is a phosphorothioate linkage, and N comprises one or morenucleosides.

191. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 5S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3′,wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methylmodified nucleoside, “s” is a phosphorothioate linkage, and N comprisesone or more nucleosides.

192. The use of any one of embodiments 157-192, wherein the antisensestrand comprises modification pattern 1AS:5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

193. The use of any one of embodiments 157-192, wherein the antisensestrand comprises modification pattern 2AS:5′-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

194. The use of any one of embodiments 157-192, wherein the antisensestrand comprises modification pattern 3AS:5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

195. The use of any one of embodiments 157-192, wherein the antisensestrand comprises modification pattern 4AS:5′-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside,and “s” is a phosphorothioate linkage.

196. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 1S and the antisense strand comprisesmodification pattern 1AS, 2AS, 3AS, or 4AS.

197. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 2S and the antisense strand comprisesmodification pattern 1AS, 2AS, 3AS, or 4AS.

198. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 3S and the antisense strand comprisesmodification pattern 1AS, 2AS, 3AS, or 4AS.

199. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 4S and the antisense strand comprisesmodification pattern 1AS, 2AS, 3AS, or 4AS.

200. The use of any one of embodiments 157-186, wherein the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acidsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions, and modification pattern 15.

201. The use of any one of embodiments 157-186, wherein the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, and modificationpattern 15.

202. The use of any one of embodiments 157-186, wherein the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acidsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions, and modification pattern 2S.

203. The use of any one of embodiments 157-186, wherein the sense strandcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 1-1854 or 13970-13977, and modificationpattern 2S.

204. The use of any one of embodiments 157-186 or 200-203, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 1AS.

205. The use of any one of embodiments 157-186 or 200-203, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, and modification pattern 1AS.

206. The use of any one of embodiments 157-186 or 200-203, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, or a nucleic acid sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions, and modification pattern 3AS.

207. The use of any one of embodiments 157-186 or 200-203, wherein theantisense strand comprises a nucleoside sequence comprising orconsisting of the sequence of any one of SEQ ID NOs: 1855-3708 or13978-13985, and modification pattern 3AS.

208. The use of any one of embodiments 90-156, wherein theoligonucleotide comprises an ASO.

209. The use of embodiment 208, wherein the ASO is 12-30 nucleosides inlength. 210. The use of any one of embodiments 90-156, wherein theoligonucleotide comprises an antisense oligonucleotide (ASO) about 12-30nucleosides in length and comprising a nucleoside sequence complementaryto about 12-30 contiguous nucleosides of SEQ ID NO: 13935.

211. The use of any one of embodiments 90-156, wherein theoligonucleotide comprises an ASO about 12-30 nucleosides in length andcomprising a nucleoside sequence complementary to about 12-30 contiguousnucleosides of SEQ ID NO: 13936.

212. The use of any one of embodiments 208-211, wherein the ASO is 15-25nucleosides in length.

213. The use of any one of embodiments 208-212, wherein the ASO is 20nucleosides in length.

214. The use of any one of embodiments 208-213, wherein the ASOcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 3709-13934, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions.

215. The use of any one of embodiments 208-214, wherein the ASOcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 3709-13934.

216. The use of any one of embodiments 208-215, wherein the ASOcomprises modification pattern:5′-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3′ where “dN” isany deoxynucleotide, “n” is a 2′O-methyl or 2′O-methoxyethyl-modifiednucleoside, and “s” is a phosphorothioate linkage.

217. The use of any one of embodiments 208-215, wherein the ASOcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 3709-13934, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions, andmodification pattern ASO1.

218. The use of any one of embodiments 208-215, wherein the ASOcomprises a nucleoside sequence comprising or consisting of the sequenceof any one of SEQ ID NOs: 3709-13934, and modification pattern ASO1.

219. The use of any one of embodiments 90-218, wherein the compositionis a pharmaceutical composition.

220. The use of any one of embodiments 90-219, wherein the compositionis sterile. 221. The use of any one of embodiments 90-220, furthercomprising a pharmaceutically acceptable carrier.

222. The use of embodiment 221, wherein the pharmaceutically acceptablecarrier comprises water, a buffer, or a saline solution.

223. The composition of any one of embodiments 28-57, wherein the sensestrand comprises modification pattern 6S.

224. The composition of any one of embodiments 28-62 or 223, wherein theantisense strand comprises modification pattern 5AS.

225. The composition of any one of embodiments 28-62 or 223, wherein theantisense strand comprises modification pattern 6AS.

226. The composition of any one of embodiments 28-62 or 223, wherein theantisense strand comprises modification pattern 7AS.

227. The composition of any one of embodiments 28-62 or 223, wherein theantisense strand comprises modification pattern 8AS.

228. The composition of any one of embodiments 28-62 or 223, wherein theantisense strand comprises modification pattern 9AS.

229. The use of any one of embodiments 157-186, wherein the sense strandcomprises modification pattern 6S.

230. The use of any one of embodiments 157-192 or 229, wherein theantisense strand comprises modification pattern 5AS.

231. The use of any one of embodiments 157-192 or 229, wherein theantisense strand comprises modification pattern 6AS.

232. The use of any one of embodiments 157-192 or 229, wherein theantisense strand comprises modification pattern 7AS.

233. The use of any one of embodiments 157-192 or 229, wherein theantisense strand comprises modification pattern 8AS.

234. The use of any one of embodiments 157-192 or 229, wherein theantisense strand comprises modification pattern 9AS.

VI. Further Embodiments

Some embodiments include one or more of the following:

1. A composition comprising an oligonucleotide that targetsAngiopoietin-like 4 (ANGPTL4) and when administered to a subject in aneffective amount decreases circulating triglycerides, decreasescirculating total cholesterol, decreases circulating glucose, increasescirculating high-density lipoproteins (HDL), or increases insulinsensitivity, wherein the oligonucleotide comprises a small interferingRNA (siRNA) comprising a sense strand and an antisense strand, theantisense strand being complementary with no more than 2 mismatches to aportion of a nucleic acid having the nucleoside sequence of SEQ ID NO:13936, and each strand having 12 to 30 nucleotides.

2. The composition of embodiment 1, wherein the triglycerides, totalcholesterol, or glucose is decreased by about 10% or more, or the HDL orinsulin sensitivity is increased by about 10% or more, as compared toprior to administration.

3. The composition of embodiment 1 or 2, wherein the antisense strand iscomplementary with no more than 2 mismatches to a portion of a nucleicacid having the nucleoside sequence of SEQ ID NO: 13935.

4. The composition of any one of embodiments 1-3, wherein the antisensestrand comprises a nucleoside sequence at least 85% identical to anyantisense strand sequence of an siRNA in Table 4.

5. The composition of any one of embodiments 1-3, wherein the antisensestrand comprises the nucleoside sequence of any antisense strandsequence of an siRNA in Table 4, or an antisense strand sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions.

6. The composition of any one of embodiments 1-3, wherein the antisensestrand comprises the nucleoside sequence of any antisense strandsequence of an siRNA in Table 4.

7. The composition of any one of embodiments 4-6, wherein the sensestrand comprises a nucleoside sequence at least 85% identical to thesense strand sequence of the siRNA in Table 4.

8. The composition of any one of embodiments 4-6, wherein the sensestrand comprises the nucleoside sequence of the sense strand sequence ofthe siRNA in Table 4, or a sense strand sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions.

9. The composition of any one of embodiments 4-6, wherein the sensestrand comprises the nucleoside sequence of the sense strand sequence ofthe siRNA in Table 4.

10. The composition of any one of embodiments 1-3, wherein the antisensestrand comprises a nucleoside sequence at least 85% identical to any oneof SEQ ID NOS: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144,2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425,2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005,3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284,3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696.

11. The composition of any one of embodiments 1-3, wherein the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOS: 1886,1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180,2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613,2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020,3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434,3435, 3443, 3451, 3465, 3556, 3694, or 3696, or an antisense strandsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions.

12. The composition of any one of embodiments 1-3, wherein the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOS: 1886,1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180,2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613,2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020,3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434,3435, 3443, 3451, 3465, 3556, 3694, or 3696.

13. The composition of any one of embodiments 10-12, wherein the sensestrand comprises a nucleoside sequence at least 85% identical to any oneof SEQ ID NOS: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323,326, 332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834,876, 1001, 1133, 1134, 1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171,1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581,1589, 1597, 1611, 1702, 1840, or 1842.

14. The composition of any one of embodiments 10-12, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOS: 32,33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484,509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134,1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285,1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702,1840, or 1842, or a sense strand sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions.

15. The composition of any one of embodiments 10-12, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOS: 32,33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484,509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134,1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285,1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702,1840, or 1842.

16. The composition of any one of embodiments 1-3, wherein the antisensestrand comprises a nucleoside sequence at least 85% identical to any oneof SEQ ID NOS: 13978-13981.

17. The composition of any one of embodiments 1-3, wherein the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOS:13978-13981, or an antisense strand sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions.

18. The composition of any one of embodiments 1-3, wherein the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOS:13978-13981.

19. The composition of any one of embodiments 16-18, wherein the sensestrand comprises a nucleoside sequence at least 85% identical to any oneof SEQ ID NOS: 13970-13973.

20. The composition of any one of embodiments 16-18, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOS:13970-13973, or a sense strand sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions.

21. The composition of any one of embodiments 16-18, wherein the sensestrand comprises the nucleoside sequence of any one of SEQ ID NOS:13970-13973.

22. The composition of any one of embodiments 1-21, wherein theoligonucleotide comprises one or more modified internucleoside linkages.

23. The composition of embodiment 22, wherein the one or more modifiedinternucleoside linkages comprise alkylphosphonate, phosphorothioate,methylphosphonate, phosphorodithioate, alkylphosphonothioate,phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate,or carboxymethyl ester, or a combination thereof.

24. The composition of embodiment 22 or 23, wherein the one or moremodified internucleoside linkages comprise a phosphorothioate linkage.

25. The composition of any one of embodiments 22-24, wherein the sensestrand comprises 2-6 modified intemucleoside linkages.

26. The composition of any one of embodiments 22-25, wherein theantisense strand comprises 2-6 modified intemucleoside linkages.

27. The composition of any one of embodiments 1-26, wherein theoligonucleotide comprises one or more modified nucleosides.

28. The composition of embodiment 27, wherein the one or more modifiednucleosides comprise a locked nucleic acid (LNA), hexitol nucleic acid(HLA), cyclohexene nucleic acid (CeNA), a 2′,4′ constrained ethyl,2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-O-allyl, 2′-fluoro,2′-deoxy, a 2′-O-methyl nucleoside, 2′-deoxyfluoro nucleoside,2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl(2′-O-AP) nucleoside, 2′-ara-F, or a combination thereof.

29. The composition of embodiment 27 or 28, wherein the one or moremodified nucleosides comprise a 2′ fluoro modified nucleoside.

30. The composition of any one of embodiments 27-29, wherein the one ormore modified nucleosides comprise a 2′ O-methyl modified nucleoside.

31. The composition of any one of embodiments 27-30, wherein the sensestrand comprises 15-21 modified nucleosides, and/or the antisense strandcomprises 15-21 modified nucleosides.

32. The composition of any one of embodiments 1-31, wherein the sensestrand or the antisense strand comprises a 3′ overhang of at least 2nucleosides.

33. The composition of any one of embodiments 1-32, wherein theoligonucleotide comprises a GalNAc ligand attached at a 3′ or 5′terminus of the sense strand.

34. The composition of any one of embodiments 1-33, wherein theoligonucleotide comprises a GalNAc ligand attached at a 3′ or 5′terminus of the antisense strand

35. The composition of any one of embodiments 1-34, wherein the sensestrand comprises modification pattern 1S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13954),modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′ (SEQ ID NO:13955), modification pattern 3S: 5′-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′ (SEQID NO: 13956), modification pattern 4S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3′ (SEQ ID NO: 13957),modification pattern 5S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3′ (SEQ IDNO: 13958); modification pattern 6S:5′-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13959); wherein“Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, “s” is a phosphorothioate linkage, and N comprises anucleoside.

36. The composition of any one of embodiments 1-35, wherein theantisense strand comprises modification pattern 1AS:5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13960), modificationpattern 2AS: 5′-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13961),modification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′ (SEQ IDNO: 13962), modification pattern 4AS:5′-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13963), modificationpattern 5AS: 5′-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13964),modification pattern 6AS: 5′-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3′ (SEQID NO: 13965), modification pattern 7AS:5′-nsNfsnNfnNfnNfNfnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13966), modificationpattern 8AS: 5′-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3′ (SEQ ID NO: 13967), ormodification pattern 9AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn-3′ (SEQ IDNO: 13968); wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

37. The composition of any one of embodiments 1-36, wherein thecomposition is a pharmaceutical composition comprising apharmaceutically acceptable carrier.

38. The composition of embodiment 37, wherein the pharmaceuticallyacceptable carrier comprises water, a buffer, or a saline solution.

39. Use of a composition comprising an oligonucleotide that targetsANGPTL4, wherein the oligonucleotide comprises a small interfering RNA(siRNA) comprising a sense strand and an antisense strand, the antisensestrand being complementary with no more than 2 mismatches to a portionof a nucleic acid having the nucleoside sequence of SEQ ID NO: 13936,and each strand having 12 to 30 nucleotides, in a method of treating ametabolic or cardiovascular disorder in a subject in need thereof, themethod comprising administering to the subject an effective amount ofthe composition.

40. The use of embodiment 39, wherein the disorder compriseshyperlipidemia, hypertriglyceridemia, diabetes, type 2 diabetes, heartdisease, a myocardial infarction, angina pectoris, or atherosclerosis.

41. The use of embodiment 39 or 40, wherein the effective amount of thecomposition decreases a triglyceride measurement, decreases acholesterol measurement, decreases a glucose measurement, increases anHDL measurement, or increases an insulin sensitivity measurement in thesubject by about 10% or more, relative to a baseline measurement.

42. The use of any one of embodiments 39-41, wherein the antisensestrand is complementary with no more than 2 mismatches to a portion of anucleic acid having the nucleoside sequence of SEQ ID NO: 13935.

43. The use of any one of embodiments 39-42, wherein the antisensestrand comprises a nucleoside sequence at least 85% identical to any oneof SEQ ID NOS: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144,2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425,2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005,3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284,3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696.

44. The use of any one of embodiments 39-42, wherein the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOS: 1886,1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180,2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613,2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020,3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434,3435, 3443, 3451, 3465, 3556, 3694, or 3696, or an antisense strandsequence thereof having 1 or 2 nucleoside substitutions, additions, ordeletions.

45. The use of any one of embodiments 39-42, wherein the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOS: 1886,1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180,2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613,2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020,3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434,3435, 3443, 3451, 3465, 3556, 3694, or 3696.

46. The use of any one of embodiments 43-45, wherein the sense strandcomprises a nucleoside sequence at least 85% identical to any one of SEQID NOS: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326,332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876,1001, 1133, 1134, 1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172,1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589,1597, 1611, 1702, 1840, or 1842.

47. The use of any one of embodiments 43-45, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOS: 32, 33, 35,36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509,519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134,1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285,1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702,1840, or 1842, ora sense strand sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions.

48. The use of any one of embodiments 43-45, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOS: 32, 33, 35,36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509,519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134,1137, 1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285,1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702,1840, or 1842.

49. The use of any one of embodiments 39-42, wherein the antisensestrand comprises a nucleoside sequence at least 85% identical to any oneof SEQ ID NOS: 13978-13981.

50. The use of any one of embodiments 39-42, wherein the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOS:13978-13981, or an antisense strand sequence thereof having 1 or 2nucleoside substitutions, additions, or deletions.

51. The use of any one of embodiments 39-42, wherein the antisensestrand comprises the nucleoside sequence of any one of SEQ ID NOS:13978-13981.

52. The use of any one of embodiments 49-51, wherein the sense strandcomprises a nucleoside sequence at least 85% identical to any one of SEQID NOS: 13970-13973.

53. The use of any one of embodiments 49-51, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOS: 13970-13973,or a sense strand sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions.

54. The use of any one of embodiments 49-51, wherein the sense strandcomprises the nucleoside sequence of any one of SEQ ID NOS: 13970-13973.

55. The use of any one of embodiments 39-54, wherein the oligonucleotidecomprises one or more modified internucleoside linkages comprisingalkylphosphonate, phosphorothioate, methylphosphonate,phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate,carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or acombination thereof.

56. The use of any one of embodiments 39-55, wherein the oligonucleotidecomprises one or more modified nucleosides comprising a locked nucleicacid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA),a 2′,4′ constrained ethyl, 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl,2′-O-allyl, 2′-fluoro, 2′-deoxy, a 2′-O-methyl nucleoside,2′-deoxyfluoro nucleoside, 2′-O—N-methylacetamido (2′-O-NMA) nucleoside,a 2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleoside,2′-O-aminopropyl (2′-O-AP) nucleoside, 2′-ara-F, or a combinationthereof.

57. The use of any one of embodiments 39-56, wherein the sense strand orthe antisense strand comprises a 3′ overhang of at least 2 nucleosides.

58. The use of any one of embodiments 39-57, wherein the oligonucleotidecomprises a GalNAc ligand attached at a 3′ or 5′ terminus of the sensestrand.

59. The use of any one of embodiments 39-58, wherein the oligonucleotidecomprises a GalNAc ligand attached at a 3′ or 5′ terminus of theantisense strand

60. The use of any one of embodiments 39-59, wherein the sense strandcomprises modification pattern 1S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13954),modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′ (SEQ ID NO:13955), modification pattern 3S: 5′-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′ (SEQID NO: 13956), modification pattern 4S:5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3′ (SEQ ID NO: 13957),modification pattern 5S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3′ (SEQ IDNO: 13958); modification pattern 6S:5′-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13959); wherein“Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, “s” is a phosphorothioate linkage, and N comprises anucleoside.

61. The use of any one of embodiments 39-60, wherein the antisensestrand comprises modification pattern 1AS:5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13960), modificationpattern 2AS: 5′-nsNfsnnnNfnNfNfnrmnNfnNfnnnsnsn-3′ (SEQ ID NO: 13961),modification pattern 3AS: 5′-nsNfsnnnNfnrmrmnnNfnNfrmnsnsn-3′ (SEQ IDNO: 13962), modification pattern 4AS:5′-nsNfsnNfnNfnnrmrmnNfnNfnnnsnsn-3′ (SEQ ID NO: 13963), modificationpattern 5AS: 5′-nsNfsnnnNfnNfrmrmnNfnNfnnnsnsn-3′ (SEQ ID NO: 13964),modification pattern 6AS: 5′-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3′ (SEQID NO: 13965), modification pattern 7AS:5′-nsNfsnNfnNfnNfNfnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13966), modificationpattern 8AS: 5′-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3′ (SEQ ID NO: 13967), ormodification pattern 9AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn-3′ (SEQ IDNO: 13968); wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

VII. Examples

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention.

Example 1: Loss of Function Variants in ANGPTL4 Are Associated withDecreased Risk of Cardiovascular and Metabolic Disease

Approximately 30,000,000 imputed variants were analyzed in 375,000individuals from the UK Biobank cohort for associations withcardiometabolic traits including circulating triglyceride levels,hyperlipidemia, chronic ischemic heart disease, myocardial infarction,Type 2 diabetes, and lipid-lowering and diabetes medication use.Additionally, rare loss of function variants were evaluated in a geneburden test in a subset of 45,000 individuals from the UK Biobank cohortwith available exome sequencing data. Case counts in the full andexome-sequenced cohorts are shown in Table 2.

TABLE 2 Case and Value Counts for Tested Cardiometabolic Traits ImputedGenotypes Exome Sequencing Trait Cases/Counts Cases/CountsHyperlipidemia 80,196 10,112 Chronic ischemic heart disease 26,771 3,135Angina pectoris 22,200 2,685 Myocardial Infarction 15,250 1,616 Type 2diabetes mellitus 20,663 2,512 Medication-simvastatin 42,197 5,404Medication-metformin 9,262 1,184 Family history of heart disease 162,65720,211 Family history of diabetes 76,202 9,845 Blood Triglycerides356,875 43,055 Blood HDL 327,461 40,600

Protective associations were observed between a low-frequency and a raremissense variant (rs116843064; MAF=0.02 and rs140744493; MAF=0.003)within ANGPTL4 and cardiometabolic traits (see Table 3). The majorallele (chr19-8429323-G, hg19) of the rs116843064 variant encodes for aglutamic acid residue and the minor allele (chr19-8429323-A, hg19) alysine at amino acid position 40 of the full length ANGPTL4 protein(Glu40Lys; E40K). A lysine at position 40 reduces the inhibition of LPLby ANGPTL4; rs116843064 is thus a loss of function variant. The majorallele (chr19-8436373-C, hg19) of the rs140744493 variant encodes for anarginine residue and the minor allele (chr19-8436373-T, hg19) a cysteineat amino acid position 336 of the full length ANGPTL4 protein(Arg336Cys; R336C). A cysteine at position 336 impairs cellularsecretion of ANGPTL4; rs140744493 is thus also a loss of functionvariant. Carriers of the minor allele of both of these variants had areduced risk of a range of cardiometabolic diseases, as well as reducedcirculating triglycerides (p=2.35×10{circumflex over ( )}−145;beta=−0.048 and p=2.64×10{circumflex over ( )}−4; beta=−0.018 forrs116843064 and rs140744493, respectively) and increased high densitylipoprotein levels (p=2.35×10{circumflex over ( )}−145; beta=−0.048 andp=2.64×10{circumflex over ( )}−4; beta=−0.018 for rs116843064 andrs140744493, respectively). Accordingly, in some cases therapeuticinhibition or modulation of ANGPTL4 may be an effectivegenetically-informed method of treatment for cardiovascular andmetabolic disease.

TABLE 3 Association of ANGPTL4 Missense Variants with CardiometabolicTraits rs116843064 (E40K) rs140744493 (R336C) Trait Effect Size P EffectSize P Hyperlipidemia 0.87 (OR) 2.04E−10  NS NS Chronic ischemic heartdisease 0.84 (OR) 1.03E−06  NS NS Angina pectoris 0.85 (OR) 1.59E−05 0.81 (OR) 0.04 Myocardial Infarction 0.85 (OR) 4.53E−04  NS NS Type 2diabetes mellitus 0.88 (OR) 7.31E−04  NS NS Medication-simvastatin 0.91(OR) 1.13E−03  0.83 (OR) 0.01 Medication-metformin 0.79 (OR) 9.11E−05 NS NS Family history of heart disease 0.95 (OR) 5.55E−03  0.91 (OR) 0.04Family history of diabetes 0.94 (OR) 2.20E−03  NS NS Blood Triglycerides−0.048 (beta) 2.35E−145 −0.018 (beta) 2.13E−04 Blood HDL  0.023 (beta)3.15E−115  0.011 (beta) 9.70E−06 NS = Not Significant, OR = Odds Ratio

Using the subset of individuals with available exome sequencing data(approximately 45,000 of the 375,000 individuals), a gene burden testwas applied to assess the association of ANGPTL4 loss of functionvariants on cardiometabolic traits. Gene burden tests are used toaggregate rare variants in a gene by functional class that are too rareto be tested individually. In total, 17 rare predicted loss of functionvariants (frameshift, stop gained and splice donor/acceptor variants) in72 total carriers were tested. Individuals carrying predicted ANGPTL4loss of function variants had significantly lower triglyceride levelswhen compared to non-carriers (p=2.64E-4; beta=−0.097). These resultsare directionally consistent with the results obtained in the largercohort for the rs116843064 and rs140744493 inactivating missensevariants, and further confirm that ANGPTL4 loss of function results inlower circulating triglyceride levels.

Example 2: Bioinformatic Selection of Sequences in Order to IdentifyTherapeutic siRNAs to Downmodulate Expression of the ANGPTL4 mRNA

Screening sets were defined based on bioinformatic analysis. TherapeuticsiRNAs were designed to target human ANGPTL4, and the ANGPTL4 sequenceof at least one toxicology-relevant species, in this case, the non-humanprimates (NHP) rhesus and cynomolgus monkeys. Drivers for the design ofthe screening set were predicted specificity of the siRNAs against thetranscriptome of the relevant species as well as cross-reactivitybetween species. Predicted specificity in human, rhesus monkey,cynomolgus monkey, mouse and rat was determined for sense (S) andantisense (AS) strands. These were assigned a “specificity score” whichconsiders the likelihood of unintended downregulation of any othertranscript by full or partial complementarity of an siRNA strand (up to4 mismatches within positions 2-18) as well as the number and positionsof mismatches. Thus, off-target(s) for antisense and sense strands ofeach siRNA were identified. In addition, the number of potentialoff-targets was used as an additional specificity factor in thespecificity score. As identified, siRNAs with high specificity and a lownumber of predicted off-targets provide a benefit of increased targetingspecificity.

In addition to selecting siRNA sequences with high sequence specificityto ANGPTL4 mRNA, siRNA sequences within the seed region were analyzedfor similarity to seed regions of known miRNAs. siRNAs can function in amiRNA like manner via base-pairing with complementary sequences withinthe 3′-UTR of mRNA molecules. The complementarity typically encompassesthe 5′-bases at positions 2-7 of the miRNA (seed region). To circumventsiRNAs to act via functional miRNA binding sites, siRNA strandscontaining natural miRNA seed regions were avoided. Seed regionsidentified in miRNAs from human, mouse, rat, rhesus monkey, dog, rabbitand pig are referred to as “conserved”. Combining the “specificityscore” with miRNA seed analysis yielded a “specificity category”. Thisis divided into categories 1-4, with 1 having the highest specificityand 4 having the lowest specificity. Each strand of the siRNA isassigned to a specificity category.

Species cross-reactivity was assessed for human, cynomolgus monkey,rhesus monkey, mouse and rat. The analysis was based on a canonicalsiRNA design using 19 bases and 17 bases (without considering positions1 and 19) for cross-reactivity. Full match as well as single mismatchanalyses were included.

Analysis of the human Single Nucleotide Polymorphism (SNP) database(NCBI-DB-SNP) to identify siRNAs targeting regions with known SNPs wasalso carried out to identify siRNAs that may be non-functional inindividuals containing the SNP. Information regarding the positions ofSNPs within the target sequence as well as minor allele frequency (MAF)in case data was obtained in this analysis.

Initial analysis of the relevant ANGPTL4 mRNA sequence revealed fewsequences that fulfil the specificity parameters and at the same timetarget ANGPTL4 mRNA in all of the analyzed relevant species. Therefore,it was decided to design independent screening subsets for thetherapeutic siRNAs.

The siRNAs in these subsets recognize the human ANGPTL4 sequence, as ahuman cell culture system is selected for determination of in vitroactivity. Therefore, the siRNAs in these subsets can be used to targethuman ANGPTL4 in a therapeutic setting.

The number of siRNAs that were derived from human ANGPTL4 mRNA(NM_139314.3) without consideration of specificity or speciescross-reactivity was 1,854 (antisense and sense strand sequencesincluded in SEQ ID NOS: 1-3708).

Prioritizing sequences for target specificity, species cross-reactivity,miRNA seed region sequences and SNPs as described above yields subset A.The siRNAs in subset A are included in Table 4.

TABLE 4 Subset A Sense Strand Antisense Strand Sequence- Sequence- siRNAName SEQ ID NO: SEQ ID NO: siRNA 32 32 1886 siRNA 33 33 1887 siRNA 34 341888 siRNA 35 35 1889 siRNA 36 36 1890 siRNA 56 56 1910 siRNA 57 57 1911siRNA 58 58 1912 siRNA 59 59 1913 siRNA 61 61 1915 siRNA 62 62 1916siRNA 63 63 1917 siRNA 64 64 1918 siRNA 79 79 1933 siRNA 80 80 1934siRNA 84 84 1938 siRNA 111 111 1965 siRNA 112 112 1966 siRNA 116 1161970 siRNA 117 117 1971 siRNA 118 118 1972 siRNA 119 119 1973 siRNA 120120 1974 siRNA 121 121 1975 siRNA 125 125 1979 siRNA 126 126 1980 siRNA127 127 1981 siRNA 128 128 1982 siRNA 129 129 1983 siRNA 149 149 2003siRNA 150 150 2004 siRNA 152 152 2006 siRNA 153 153 2007 siRNA 154 1542008 siRNA 157 157 2011 siRNA 158 158 2012 siRNA 159 159 2013 siRNA 161161 2015 siRNA 164 164 2018 siRNA 165 165 2019 siRNA 166 166 2020 siRNA167 167 2021 siRNA 168 168 2022 siRNA 169 169 2023 siRNA 172 172 2026siRNA 174 174 2028 siRNA 175 175 2029 siRNA 177 177 2031 siRNA 196 1962050 siRNA 198 198 2052 siRNA 199 199 2053 siRNA 210 210 2064 siRNA 211211 2065 siRNA 212 212 2066 siRNA 214 214 2068 siRNA 215 215 2069 siRNA216 216 2070 siRNA 217 217 2071 siRNA 218 218 2072 siRNA 219 219 2073siRNA 221 221 2075 siRNA 222 222 2076 siRNA 223 223 2077 siRNA 228 2282082 siRNA 230 230 2084 siRNA 231 231 2085 siRNA 240 240 2094 siRNA 241241 2095 siRNA 245 245 2099 siRNA 246 246 2100 siRNA 250 250 2104 siRNA252 252 2106 siRNA 253 253 2107 siRNA 254 254 2108 siRNA 255 255 2109siRNA 260 260 2114 siRNA 261 261 2115 siRNA 262 262 2116 siRNA 263 2632117 siRNA 265 265 2119 siRNA 266 266 2120 siRNA 271 271 2125 siRNA 272272 2126 siRNA 274 274 2128 siRNA 280 280 2134 siRNA 282 282 2136 siRNA289 289 2143 siRNA 290 290 2144 siRNA 291 291 2145 siRNA 292 292 2146siRNA 293 293 2147 siRNA 299 299 2153 siRNA 304 304 2158 siRNA 321 3212175 siRNA 323 323 2177 siRNA 325 325 2179 siRNA 326 326 2180 siRNA 328328 2182 siRNA 329 329 2183 siRNA 330 330 2184 siRNA 331 331 2185 siRNA332 332 2186 siRNA 333 333 2187 siRNA 334 334 2188 siRNA 335 335 2189siRNA 337 337 2191 siRNA 338 338 2192 siRNA 339 339 2193 siRNA 342 3422196 siRNA 347 347 2201 siRNA 349 349 2203 siRNA 350 350 2204 siRNA 352352 2206 siRNA 353 353 2207 siRNA 356 356 2210 siRNA 377 377 2231 siRNA380 380 2234 siRNA 382 382 2236 siRNA 386 386 2240 siRNA 388 388 2242siRNA 391 391 2245 siRNA 392 392 2246 siRNA 393 393 2247 siRNA 394 3942248 siRNA 397 397 2251 siRNA 398 398 2252 siRNA 399 399 2253 siRNA 402402 2256 siRNA 404 404 2258 siRNA 405 405 2259 siRNA 411 411 2265 siRNA412 412 2266 siRNA 413 413 2267 siRNA 414 414 2268 siRNA 415 415 2269siRNA 417 417 2271 siRNA 419 419 2273 siRNA 420 420 2274 siRNA 421 4212275 siRNA 422 422 2276 siRNA 423 423 2277 siRNA 424 424 2278 siRNA 425425 2279 siRNA 426 426 2280 siRNA 427 427 2281 siRNA 428 428 2282 siRNA429 429 2283 siRNA 430 430 2284 siRNA 431 431 2285 siRNA 435 435 2289siRNA 481 481 2335 siRNA 484 484 2338 siRNA 506 506 2360 siRNA 509 5092363 siRNA 517 517 2371 siRNA 519 519 2373 siRNA 520 520 2374 siRNA 565565 2419 siRNA 570 570 2424 siRNA 571 571 2425 siRNA 572 572 2426 siRNA589 589 2443 siRNA 607 607 2461 siRNA 608 608 2462 siRNA 610 610 2464siRNA 611 611 2465 siRNA 612 612 2466 siRNA 616 616 2470 siRNA 617 6172471 siRNA 620 620 2474 siRNA 623 623 2477 siRNA 635 635 2489 siRNA 637637 2491 siRNA 640 640 2494 siRNA 643 643 2497 siRNA 653 653 2507 siRNA672 672 2526 siRNA 673 673 2527 siRNA 674 674 2528 siRNA 675 675 2529siRNA 676 676 2530 siRNA 677 677 2531 siRNA 678 678 2532 siRNA 679 6792533 siRNA 681 681 2535 siRNA 682 682 2536 siRNA 683 683 2537 siRNA 684684 2538 siRNA 686 686 2540 siRNA 687 687 2541 siRNA 689 689 2543 siRNA692 692 2546 siRNA 695 695 2549 siRNA 830 830 2684 siRNA 834 834 2688siRNA 841 841 2695 siRNA 842 842 2696 siRNA 843 843 2697 siRNA 844 8442698 siRNA 850 850 2704 siRNA 851 851 2705 siRNA 852 852 2706 siRNA 853853 2707 siRNA 854 854 2708 siRNA 856 856 2710 siRNA 857 857 2711 siRNA859 859 2713 siRNA 866 866 2720 siRNA 868 868 2722 siRNA 871 871 2725siRNA 872 872 2726 siRNA 876 876 2730 siRNA 887 887 2741 siRNA 888 8882742 siRNA 890 890 2744 siRNA 892 892 2746 siRNA 893 893 2747 siRNA 894894 2748 siRNA 897 897 2751 siRNA 900 900 2754 siRNA 902 902 2756 siRNA907 907 2761 siRNA 911 911 2765 siRNA 912 912 2766 siRNA 913 913 2767siRNA 914 914 2768 siRNA 915 915 2769 siRNA 916 916 2770 siRNA 917 9172771 siRNA 918 918 2772 siRNA 919 919 2773 siRNA 920 920 2774 siRNA 921921 2775 siRNA 922 922 2776 siRNA 925 925 2779 siRNA 945 945 2799 siRNA968 968 2822 siRNA 1001 1001 2855 siRNA 1002 1002 2856 siRNA 1005 10052859 siRNA 1006 1006 2860 siRNA 1009 1009 2863 siRNA 1010 1010 2864siRNA 1011 1011 2865 siRNA 1013 1013 2867 siRNA 1028 1028 2882 siRNA1032 1032 2886 siRNA 1037 1037 2891 siRNA 1052 1052 2906 siRNA 1053 10532907 siRNA 1054 1054 2908 siRNA 1055 1055 2909 siRNA 1057 1057 2911siRNA 1058 1058 2912 siRNA 1064 1064 2918 siRNA 1112 1112 2966 siRNA1122 1122 2976 siRNA 1124 1124 2978 siRNA 1126 1126 2980 siRNA 1127 11272981 siRNA 1133 1133 2987 siRNA 1134 1134 2988 siRNA 1136 1136 2990siRNA 1137 1137 2991 siRNA 1147 1147 3001 siRNA 1148 1148 3002 siRNA1149 1149 3003 siRNA 1151 1151 3005 siRNA 1153 1153 3007 siRNA 1154 11543008 siRNA 1155 1155 3009 siRNA 1157 1157 3011 siRNA 1158 1158 3012siRNA 1161 1161 3015 siRNA 1162 1162 3016 siRNA 1163 1163 3017 siRNA1164 1164 3018 siRNA 1165 1165 3019 siRNA 1166 1166 3020 siRNA 1171 11713025 siRNA 1172 1172 3026 siRNA 1175 1175 3029 siRNA 1181 1181 3035siRNA 1182 1182 3036 siRNA 1184 1184 3038 siRNA 1248 1248 3102 siRNA1249 1249 3103 siRNA 1252 1252 3106 siRNA 1253 1253 3107 siRNA 1259 12593113 siRNA 1276 1276 3130 siRNA 1285 1285 3139 siRNA 1310 1310 3164siRNA 1315 1315 3169 siRNA 1338 1338 3192 siRNA 1343 1343 3197 siRNA1347 1347 3201 siRNA 1348 1348 3202 siRNA 1349 1349 3203 siRNA 1350 13503204 siRNA 1351 1351 3205 siRNA 1352 1352 3206 siRNA 1378 1378 3232siRNA 1405 1405 3259 siRNA 1407 1407 3261 siRNA 1413 1413 3267 siRNA1414 1414 3268 siRNA 1415 1415 3269 siRNA 1416 1416 3270 siRNA 1417 14173271 siRNA 1418 1418 3272 siRNA 1429 1429 3283 siRNA 1430 1430 3284siRNA 1448 1448 3302 siRNA 1477 1477 3331 siRNA 1487 1487 3341 siRNA1488 1488 3342 siRNA 1489 1489 3343 siRNA 1493 1493 3347 siRNA 1494 14943348 siRNA 1519 1519 3373 siRNA 1523 1523 3377 siRNA 1538 1538 3392siRNA 1556 1556 3410 siRNA 1561 1561 3415 siRNA 1563 1563 3417 siRNA1564 1564 3418 siRNA 1565 1565 3419 siRNA 1570 1570 3424 siRNA 1571 15713425 siRNA 1572 1572 3426 siRNA 1580 1580 3434 siRNA 1581 1581 3435siRNA 1589 1589 3443 siRNA 1597 1597 3451 siRNA 1598 1598 3452 siRNA1601 1601 3455 siRNA 1602 1602 3456 siRNA 1603 1603 3457 siRNA 1604 16043458 siRNA 1605 1605 3459 siRNA 1606 1606 3460 siRNA 1610 1610 3464siRNA 1611 1611 3465 siRNA 1613 1613 3467 siRNA 1614 1614 3468 siRNA1617 1617 3471 siRNA 1693 1693 3547 siRNA 1699 1699 3553 siRNA 1701 17013555 siRNA 1702 1702 3556 siRNA 1703 1703 3557 siRNA 1722 1722 3576siRNA 1740 1740 3594 siRNA 1741 1741 3595 siRNA 1742 1742 3596 siRNA1745 1745 3599 siRNA 1747 1747 3601 siRNA 1748 1748 3602 siRNA 1749 17493603 siRNA 1751 1751 3605 siRNA 1754 1754 3608 siRNA 1755 1755 3609siRNA 1779 1779 3633 siRNA 1780 1780 3634 siRNA 1784 1784 3638 siRNA1787 1787 3641 siRNA 1788 1788 3642 siRNA 1798 1798 3652 siRNA 1799 17993653 siRNA 1800 1800 3654 siRNA 1801 1801 3655 siRNA 1802 1802 3656siRNA 1803 1803 3657

Subset A includes 102 siRNA sequences that are cross-reactive with NHPANGPTL4 mRNA (siRNAs 33, 34, 35, 36, 56, 121, 272, 280, 282, 289, 290,291, 292, 293, 321, 323, 326, 328, 329, 330, 331, 332, 333, 334, 335,337, 338, 339, 342, 347, 349, 411, 412, 430, 431, 435, 481, 484, 509,517, 519, 520, 565, 620, 635, 637, 640, 830, 834, 841, 842, 843, 844,850, 871, 872, 876, 887, 888, 894, 897, 902, 945, 1001, 1002, 1005,1037, 1133, 1134, 1137, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161,1162, 1164, 1165, 1166, 1171, 1172, 1248, 1249, 1315, 1338, 1343, 1347,1348, 1429, 1430, 1570, 1571, 1572, 1610, 1611, 1617, 1780, 1784, and1787). The siRNAs in subset A that may be cross-reactive with NHPANGPTL4 mRNA were tested in vitro (see, e.g., Table 5). In some cases,the sense strand of any of these siRNAs comprises modification pattern1S. In some cases, the antisense strand of any of these siRNAs comprisesmodification pattern 1AS.

The siRNAs in subset A have the following characteristics:

-   -   Cross-reactivity: With 19mer in human ANGPTL4 mRNA, with        17mer/19mer in NHP ANGPTL4    -   Specificity category: For human and NHP: AS2 or better, SS3 or        better    -   miRNA seeds: AS+SS strand: seed region not conserved in human,        mouse, and rat and not present in ≥4 species    -   Off-target frequency: ≤20 human off-targets matched with 2        mismatches in antisense strand    -   SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos.        2-18)

The siRNA sequences in subset A were selected for more stringentspecificity to yield subset B. Subset B includes 323 siRNAs (siRNAs 32,33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 112, 116, 117,118, 119, 120, 125, 126, 127, 128, 129, 149, 150, 152, 153, 157, 158,159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 196, 199, 211,212, 214, 215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240,241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266,271, 272, 274, 280, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325,326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347,349, 350, 352, 353, 356, 380, 382, 386, 388, 391, 392, 393, 394, 397,398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 420, 421, 422, 423,424, 425, 426, 427, 428, 429, 430, 431, 435, 484, 517, 519, 520, 565,570, 571, 572, 607, 608, 610, 611, 612, 616, 617, 620, 635, 637, 640,672, 673, 674, 675, 676, 677, 678, 679, 681, 682, 683, 684, 686, 687,689, 692, 695, 830, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856,857, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 902, 911,912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 945, 1001, 1002,1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1052, 1053, 1054, 1055,1057, 1058, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1147, 1148, 1149,1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1175,1182, 1184, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1343, 1347, 1348,1349, 1350, 1351, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429,1430, 1448, 1519, 1523, 1556, 1561, 1563, 1564, 1565, 1571, 1572, 1580,1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1611, 1613, 1614,1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748,1749, 1751, 1754, 1755, 1779, 1780, 1784, 1788, 1798, 1799, 1801, 1802,and 1803). This subset includes 85 siRNA sequences that arecross-reactive with NHP ANGPTL4 mRNA (siRNAs 33, 34, 35, 36, 56, 272,280, 289, 290, 291, 292, 293, 321, 323, 326, 328, 329, 330, 331, 332,333, 334, 335, 337, 338, 339, 342, 347, 349, 411, 412, 430, 431, 435,484, 517, 519, 520, 565, 620, 635, 637, 640, 830, 841, 842, 843, 844,850, 871, 872, 876, 887, 888, 894, 902, 945, 1001, 1002, 1005, 1133,1134, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165,1166, 1315, 1343, 1347, 1348, 1429, 1430, 1571, 1572, 1611, 1780, and1784).

The siRNAs in subset B have the following characteristics:

-   -   Cross-reactivity: With 19mer in human ANGPTL4 mRNA, with        17mer/19mer in NHP ANGPTL4    -   Specificity category: For human and NHP: AS2 or better, SS3 or        better    -   miRNA seeds: AS+SS strand: seed region not conserved in human,        mouse, and rat and not present in >4 species    -   Off-target frequency: ≤15 human off-targets matched with 2        mismatches in antisense strand    -   SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos.        2-18)

The siRNA sequences in subset B were further selected for absence ofseed regions in the AS strand that are identical to a seed region ofknown human miRNA to yield subset C. Subset C includes 183 siRNAs(siRNAs 32, 36, 56, 57, 58, 61, 62, 79, 80, 117, 119, 125, 126, 128,149, 152, 157, 158, 159, 161, 165, 166, 167, 168, 169, 174, 196, 211,212, 217, 218, 219, 230, 231, 245, 246, 253, 260, 261, 262, 271, 272,280, 289, 291, 292, 293, 304, 321, 323, 325, 326, 328, 330, 331, 332,333, 334, 337, 338, 342, 347, 349, 352, 353, 356, 380, 382, 386, 388,391, 392, 394, 399, 413, 414, 415, 422, 423, 424, 425, 426, 435, 517,519, 520, 565, 571, 607, 608, 612, 617, 620, 635, 640, 672, 673, 674,675, 678, 679, 681, 683, 684, 687, 692, 842, 843, 850, 851, 854, 866,868, 876, 892, 893, 902, 911, 912, 913, 914, 916, 919, 945, 1001, 1002,1006, 1010, 1028, 1052, 1053, 1054, 1055, 1057, 1112, 1124, 1127, 1147,1149, 1151, 1153, 1155, 1157, 1164, 1175, 1182, 1184, 1259, 1276, 1285,1315, 1343, 1349, 1350, 1351, 1405, 1407, 1413, 1415, 1418, 1564, 1571,1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1613, 1614, 1693,1701, 1722, 1740, 1745, 1751, 1755, 1801, 1802, and 1803). This subsetincludes 47 siRNA sequences that are cross-reactive with NHP ANGPTL4mRNA (siRNAs 36, 56, 272, 280, 289, 291, 292, 293, 321, 323, 326, 328,330, 331, 332, 333, 334, 337, 338, 342, 347, 349, 435, 517, 519, 520,565, 620, 635, 640, 842, 843, 850, 876, 902, 945, 1001, 1002, 1149,1151, 1153, 1155, 1157, 1164, 1315, 1343, and 1571).

The siRNAs in subset C have the following characteristics:

-   -   Cross-reactivity: With 19mer in human ANGPTL4 mRNA, with        17mer/19mer in NHP ANGPTL4    -   Specificity category: For human and NHP: AS2 or better, SS3 or        better    -   miRNA seeds: AS+SS strand: seed region not conserved in human,        mouse, and rat and not present in >4 species. AS strand: seed        region not identical to seed region of known human miRNA    -   Off-target frequency: ≤15 human off-targets matched with 2        mismatches by antisense strand    -   SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos.        2-18)

The siRNA sequences in subset C were also selected for absence of seedregions in the AS or S strands that are identical to a seed region ofknown human miRNA to yield subset D. Subset D includes 114 siRNAs(siRNAs 32, 36, 56, 58, 61, 62, 80, 117, 119, 126, 152, 154, 157, 158,159, 161, 166, 169, 174, 177, 196, 211, 212, 217, 218, 230, 231, 245,253, 260, 261, 271, 272, 280, 289, 293, 304, 328, 330, 331, 332, 333,334, 337, 342, 347, 349, 353, 356, 386, 388, 391, 392, 394, 414, 415,422, 423, 424, 426, 435, 520, 571, 608, 612, 617, 653, 672, 678, 679,681, 683, 692, 842, 843, 851, 854, 859, 876, 892, 900, 913, 914, 919,968, 1001, 1002, 1054, 1057, 1064, 1112, 1124, 1157, 1164, 1182, 1184,1248, 1259, 1343, 1351, 1352, 1415, 1418, 1564, 1581, 1602, 1614, 1693,1701, 1722, 1740, 1751, 1755, and 1787). This subset includes 26 siRNAsequences that are cross-reactive with NHP ANGPTL4 mRNA (siRNAs 36, 56,272, 280, 289, 293, 328, 330, 331, 332, 333, 334, 337, 342, 347, 349,435, 520, 842, 843, 876, 1001, 1002, 1157, 1164, and 1343).

The siRNAs in subset D have the following characteristics:

-   -   Cross-reactivity: With 19mer in human ANGPTL4 mRNA, with        17mer/19mer in NHP ANGPTL4    -   Specificity category: For human and NHP: AS2 or better, SS3 or        better    -   miRNA seeds: AS+SS strand: seed region not conserved in human,        mouse, and rat and not present in >4 species. AS+SS strand: seed        region not identical to seed region of known human miRNA    -   Off-target frequency: ≤20 human off-targets matched with 2        mismatches by antisense strand    -   SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos.        2-18)

The siRNA sequences in subset D were further selected for more stringentspecificity to yield subset E. Subset E includes 104 siRNAs (siRNAs 32,36, 56, 58, 61, 62, 80, 117, 119, 126, 152, 157, 158, 159, 161, 166,169, 174, 196, 211, 212, 217, 218, 230, 231, 245, 253, 260, 261, 271,272, 280, 289, 293, 304, 328, 330, 331, 332, 333, 334, 337, 342, 347,349, 353, 356, 386, 388, 391, 392, 394, 414, 415, 422, 423, 424, 426,435, 520, 571, 608, 612, 617, 672, 678, 679, 681, 683, 692, 842, 843,851, 854, 876, 892, 913, 914, 919, 1001, 1002, 1054, 1057, 1112, 1124,1157, 1164, 1182, 1184, 1259, 1343, 1351, 1415, 1418, 1564, 1581, 1602,1614, 1693, 1701, 1722, 1740, 1751, and 1755). This set includes 26siRNA sequences that are cross-reactive with NHP ANGPTL4 mRNA (siRNAs36, 56, 272, 280, 289, 293, 328, 330, 331, 332, 333, 334, 337, 342, 347,349, 435, 520, 842, 843, 876, 1001, 1002, 1157, 1164, and 1343).

The siRNAs in subset E have the following characteristics:

-   -   Cross-reactivity: With 19mer in human ANGPTL4 mRNA, with        17mer/19mer in NHP ANGPTL4    -   Specificity category: For human and NHP: AS2 or better, SS3 or        better    -   miRNA seeds: AS+SS strand: seed region not conserved in human,        mouse, and rat and not present in >4 species. AS+SS strand: seed        region not identical to seed region of known human miRNA    -   Off-target frequency: ≤15 human off-targets matched with 2        mismatches by antisense strand    -   SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos.        2-18)

The siRNA sequences targeting ANGPTL4 can also be selected using othercriteria. Subset F includes 115 siRNAs (siRNAs 32, 57, 119, 120, 125,126, 127, 128, 164, 165, 166, 167, 168, 169, 174, 175, 176, 177, 199,250, 252, 255, 260, 261, 262, 263, 353, 356, 363, 372, 403, 404, 412,413, 417, 423, 424, 425, 426, 427, 428, 429, 565, 570, 571, 572, 589,607, 608, 610, 611, 612, 672, 673, 674, 675, 676, 677, 678, 679, 689,695, 759, 801, 851, 852, 853, 854, 857, 859, 866, 868, 907, 911, 912,913, 914, 915, 918, 919, 972, 1006, 1009, 1010, 1011, 1013, 1028, 1034,1037, 1048, 1126, 1276, 1285, 1349, 1489, 1490, 1564, 1565, 1580, 1581,1589, 1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1701, 1702,1789, 1840, and 1842).

The siRNAs in subset F met the following criteria:

-   -   Cross-reactivity: With 19mer in human ANGPTL4 mRNA. One or fewer        mismatches with 19mer in either rhesus or cynomolgus monkey.    -   Specificity category: For human: AS2 or better, SS3 or better.        For NHP: AS3 or better, SS3 or better    -   miRNA seeds: AS+SS strand: seed region conserved in <4 species        (out of 7). AS and SS strand: seed region not conserved between        human, mouse and rat    -   Off-target frequency: For human: no perfect match or single        mismatches. For NHP: no perfect match    -   SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos.        2-18)

Subset G includes 20 siRNAs (siRNAs 32, 570, 571, 572, 589, 607, 759,801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1702, 1840,and 1842). The siRNAs in subset G include siRNAs from subset F that weretested in vitro (see, e.g., Table 6). In some cases, the sense strand ofany of the siRNAs of subset G comprises modification pattern 2S. In somecases, the antisense strand of any of the siRNAs of subset G comprisesmodification pattern 3AS. The siRNAs in subset G may comprise any othermodification pattern(s).

Any siRNA among any of subsets A-G may comprise any modification patterndescribed herein. If a sequence is a different number of nucleotides inlength than a modification pattern, the modification pattern may stillbe used with the appropriate number of additional nucleotides added 5′or 3′ to match the number of nucleotides in the modification pattern.For example, if a sense or antisense strand of the siRNA among any ofsubsets A-G comprises 19 nucleotides, and a modification patterncomprises 21 nucleotides, UU may be added onto the 5′ end of the senseor antisense strand.

Example 3: Chemically Modified ANGPTL4 siRNAs

The siRNAs targeting ANGPTL4 can be synthesized with chemicalmodifications with the sense strand having modification pattern 1S (SEQID NO: 13954) and the antisense strand having modification pattern 1AS(SEQ ID NO: 13960). In addition, adenosine can be placed at position 19in the sense strand and uridine at position 1 in the antisense strand.

The siRNAs targeting ANGPTL4 can also be synthesized with chemicalmodifications with the sense strand having modification pattern 2S (SEQID NO: 13955) and the antisense strand having modification pattern 3AS(SEQ ID NO: 13962). In addition, adenosine can be placed at position 19in the sense strand and uridine at position 1 in the antisense strand.

The siRNAs targeting ANGPTL4 can also be synthesized with chemicalmodifications with the sense strand having modification pattern 2S (SEQID NO: 13955) and the antisense strand having modification pattern 9AS(SEQ ID NO: 13968). In addition, adenosine can be placed at position 19in the sense strand and uridine at position 1 in the antisense strand.

The siRNAs targeting ANGPTL4 can also be synthesized with chemicalmodifications with the sense strand having modification pattern 3S (SEQID NO: 13954) and the antisense strand having modification pattern 3AS(SEQ ID NO: 13962). In addition, adenosine can be placed at position 19in the sense strand and uridine at position 1 in the antisense strand.

Example 4: Screening ANGPTL4 siRNAs for Activity in Cells in Culture

Chemically modified ANGPTL4 siRNAs cross reactive for human andnon-human primate were assayed for ANGPTL4 mRNA knockdown activity incells in culture. U-138 MG (ATCC® HTB-16) cells were seeded in 96-welltissue culture plates at a cell density of 7,500 cells per well in EMEM(BD Biosciences Catalog No. 670086) supplemented with 10% fetal bovineserum and incubated overnight in a water-jacketed, humidified incubatorat 37° C. in an atmosphere composed of air plus 5% carbon dioxide. TheANGPTL4 siRNAs were individually transfected into U-138 MG cells induplicate wells at 10 nM final concentration using 0.3 μL LipofectamineRNAiMax (Fisher) per well. Silencer Select Negative Control #1(ThermoFisher, Catalog #4390843) was transfected at 10 nM finalconcentration as a control. After incubation for 48 hours at 37° C.,total RNA was harvested from each well and cDNA prepared using TaqMan®Fast Advanced Cells-to-CT™ Kit (ThermoFisher, Catalog #A35374) accordingto the manufacturer's instructions. The level of ANGPTL4 mRNA from eachwell was measured in triplicate by real-time qPCR on an AppliedBiosystems 7500 Fast Real-Time PCR machine using TaqMan Gene ExpressionAssay for human ANGPTL4 (ThermoFisher, assay #Hs01101127 m1). The levelof PPIA mRNA was measured using TaqMan Gene Expression Assay(ThermoFisher, assay #Hs99999904 ml) and used to determine relativeANGPTL4 mRNA levels in each well using the delta-delta Ct method. Alldata were normalized to relative ANGPTL4 mRNA levels in untreated U-138MG cells. A subset of the siRNAs were also tested at 1 nM concentration.Results are shown in Table 5 and Table 6. The siRNAs in Table 5(ETD00646-ETD00747) each comprised a sense strand having modificationpattern 1S, and an sense strand having modification pattern 1AS. ThesiRNAs in Table 6 (ETD00915-ETD00934) each comprised a sense strandhaving modification pattern 2S, and an sense strand having modificationpattern 3AS.

TABLE 5 Knockdown Activity of ANGPTL4-Specific siRNAs at 1 nM and 10 nMin Human U-138 MG cells Sense Strand Antisense Strand Relative ANGPTL4mRNA Level siRNA name SEQ ID NO: SEQ ID NO: 1 nM siRNA 10 nM siRNAUntreated Cells — — 1.00 1.00 Negative — — 1.15 1.14 Control siRNAETD00646 14012 14167 ND 0.72 ETD00647 14013 14168 ND 0.97 ETD00648 1401414169 ND 0.84 ETD00649 14015 14170 0.94 0.69 ETD00650 14016 14171 ND2.08 ETD00651 14017 14172 0.99 0.71 ETD00652 14018 14173 ND 1.06ETD00653 14019 14174 1.03 0.63 ETD00654 14020 14175 1.18 0.68 ETD0065514021 14176 1.05 0.65 ETD00656 14022 14177 ND 0.86 ETD00657 14023 14178ND 0.96 ETD00658 14024 14179 ND 0.87 ETD00659 14025 14180 ND 1.02ETD00660 14026 14181 ND 0.84 ETD00661 14027 14182 ND 0.84 ETD00662 1402814183 ND 0.82 ETD00663 14029 14184 ND 0.94 ETD00664 14030 14185 ND 0.97ETD00665 14031 14186 ND 1.22 ETD00666 14032 14187 ND 1.24 ETD00667 1403314188 ND 0.88 ETD00668 14034 14189 ND 1.00 ETD00669 14035 14190 1.050.68 ETD00670 14036 14191 ND 0.93 ETD00671 14037 14192 ND 1.59 ETD0067214038 14193 ND 1.41 ETD00673 14039 14194 ND 1.80 ETD00674 14040 14195 ND1.87 ETD00675 14041 14196 ND 1.04 ETD00676 14042 14197 ND 1.28 ETD0067714043 14198 ND 1.39 ETD00678 14044 14199 ND 1.49 ETD00679 14045 14200 ND1.28 ETD00680 14046 14201 ND 1.52 ETD00681 14047 14202 ND 2.12 ETD0068214048 14203 ND 0.91 ETD00683 14049 14204 1.06 0.47 ETD00684 14050 142050.88 0.63 ETD00685 14051 14206 ND 1.02 ETD00686 14052 14207 0.79 0.66ETD00687 14053 14208 ND 0.91 ETD00688 14054 14209 ND 0.84 ETD00689 1405514210 1.01 0.51 ETD00690 14056 14211 ND 1.29 ETD00691 14057 14212 ND0.80 ETD00692 14058 14213 ND 0.78 ETD00693 14059 14214 ND 1.09 ETD0069414060 14215 1.16 0.58 ETD00695 14061 14216 ND 1.79 ETD00696 14062 14217ND 1.55 ETD00697 14063 14218 ND 1.42 ETD00698 14064 14219 ND 1.83ETD00699 14065 14220 ND 1.10 ETD00700 14066 14221 ND 1.33 ETD00701 1406714222 ND 1.13 ETD00702 14068 14223 ND 0.85 ETD00703 14069 14224 ND 1.26ETD00704 14070 14225 ND 1.14 ETD00705 14071 14226 ND 1.72 ETD00706 1407214227 ND 1.63 ETD00707 14073 14228 ND 0.92 ETD00708 14074 14229 ND 1.69ETD00709 14075 14230 1.24 0.69 ETD00710 14076 14231 ND 2.23 ETD0071114077 14232 ND 1.02 ETD00712 14078 14233 ND 1.21 ETD00713 14079 142341.09 0.48 ETD00714 14080 14235 0.94 0.50 ETD00715 14081 14236 0.98 0.65ETD00716 14082 14237 0.91 0.59 ETD00717 14083 14238 ND 0.82 ETD0071814084 14239 ND 1.09 ETD00719 14085 14240 ND 0.84 ETD00720 14086 14241 ND1.82 ETD00721 14087 14242 0.64 0.47 ETD00722 14088 14243 ND 1.52ETD00723 14089 14244 ND 1.08 ETD00724 14090 14245 ND 0.91 ETD00725 1409114246 ND 0.93 ETD00726 14092 14247 ND 0.90 ETD00727 14093 14248 ND 0.76ETD00728 14094 14249 0.94 0.43 ETD00729 14095 14250 1.08 0.71 ETD0073014096 14251 ND 0.80 ETD00731 14097 14252 1.25 0.56 ETD00732 14098 14253ND 1.25 ETD00733 14099 14254 ND 0.88 ETD00734 14100 14255 ND 1.15ETD00735 14101 14256 ND 1.11 ETD00736 14102 14257 0.90 0.48 ETD0073714103 14258 ND 1.10 ETD00738 14104 14259 ND 0.83 ETD00739 14105 14260 ND1.33 ETD00740 14106 14261 ND 1.40 ETD00741 14107 14262 ND 0.96 ETD0074214108 14263 ND 1.30 ETD00743 14109 14264 1.04 0.63 ETD00744 14110 14265ND 1.24 ETD00745 14111 14266 ND 1.42 ETD00746 14112 14267 ND 1.20ETD00747 14113 14268 ND 1.21 “—” untreated U-138MG cells; NegativeControl siRNA, Silencer Select Negative Control #1; ND, Not Determined

TABLE 6 Knockdown Activity of ANGPTL4-Specific siRNAs at 1 nM and 10 nMin Human U-138 MG Cells Antisense Relative ANGPTL4 mRNA Sense StrandStrand Level siRNA name SEQ ID NO: SEQ ID NO: 1 nM siRNA 10 nM siRNAUntreated Cells — — 1.00 1.00 Negative — — 1.23 1.10 Control siRNAETD00915 14114 14269 1.05 0.85 ETD00916 14115 14270 0.62 0.39 ETD0091714116 14271 0.84 0.86 ETD00918 14117 14272 1.02 1.03 ETD00919 1411814273 1.01 1.02 ETD00920 14119 14274 0.91 1.15 ETD00921 14120 14275 0.780.48 ETD00922 14121 14276 1.18 1.10 ETD00923 14122 14277 0.91 0.93ETD00924 14123 14278 0.82 0.57 ETD00925 14124 14279 0.79 0.57 ETD0092614125 14280 0.77 0.47 ETD00927 14126 14281 0.98 0.73 ETD00928 1412714282 0.87 0.50 ETD00929 14128 14283 0.91 0.54 ETD00930 14129 14284 0.850.58 ETD00931 14130 14285 0.85 0.46 ETD00932 14131 14286 1.01 0.72ETD00933 14132 14287 0.38 0.33 ETD00934 14133 14288 0.65 0.37 “—”untreated U-138MG cells; Negative Control siRNA, Silencer SelectNegative Control #1; ND, Not Determined

Example 5: Determining the IC50 of ANGPTL4 siRNAs

The IC50 values for knockdown of ANGPTL4 mRNA by select ANGPTL4 siRNAswere determined in U-138 MG cells. The siRNAs were assayed individuallyat 30 nM, 10 nM, 3 nM, 1 nM and 0.3 nM, or 3 nM, 1 nM, 0.3 nM, 0.1 nMand 0.03 nM, or 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, 0.1 nM and 0.03 nM.The U-138 MG (ATCC® HTB-16) cells were seeded in 96-well tissue cultureplates at a cell density of 7,500 cells per well in EMEM (BD BiosciencesCatalog No. 670086) supplemented with 10% fetal bovine serum andincubated overnight in a water-jacketed, humidified incubator at 37° C.in an atmosphere composed of air plus 5% carbon dioxide. The ANGPTL4siRNAs were individually transfected into U-138 MG cells in triplicatewells using 0.3 μL Lipofectamine RNAiMax (Fisher) per well. Afterincubation for 48 hours at 37° C., total RNA was harvested from eachwell and cDNA prepared using TaqMan® Fast Advanced Cells-to-CT™ Kit(ThermoFisher, Catalog #A35374) according to the manufacturer'sinstructions. The level of ANGPTL4 mRNA from each well was measured intriplicate by real-time qPCR on an Applied Biosystems 7500 FastReal-Time PCR machine using TaqMan Gene Expression Assay for humanANGPTL4 (ThermoFisher, assay #Hs01101127 ml). The level of PPIA mRNA wasmeasured using TaqMan Gene Expression Assay (ThermoFisher, assay#Hs99999904 ml) and used to determine relative ANGPTL4 mRNA levels ineach well using the delta-delta Ct method. All data were normalized torelative ANGPTL4 mRNA levels in untreated U-138 MG cells. Curve fit wasaccomplish using the [inhibitor] vs. response (three parameters)function in GraphPad Prism software. Results are shown in Table 7.

TABLE 7 IC50 Values of ANGPTL4 siRNAs in Human U-138 MG Cells RelativeANGPTL4 siRNA [siRNA] mRNA Levels IC50 (nM) — — 1   ND ETD00714   30 nM0.27 4.27   10 nM 0.43   3 nM 0.52   1 nM 0.69  0.3 nM 0.75 ETD00721  30 nM 0.54 2.69   10 nM 0.61   3 nM 0.86   1 nM 1.09  0.3 nM 1.21ETD00728   30 nM 0.57 5.10   10 nM 0.79   3 nM 0.95   1 nM 1.29  0.3 nM1.27 ETD00736   30 nM 0.35 8.06   10 nM 0.36   3 nM 0.76   1 nM 0.71 0.3 nM 0.78 ETD00916   3 nM 0.20 0.42   1 nM 0.45  0.3 nM 0.68  0.1 nM0.89 0.03 nM 1.07 ETD00921   30 nM 0.43 0.16   10 nM 0.43   3 nM 0.49  1 nM 0.55  0.3 nM 0.86  0.1 nM 0.93 0.03 nM 1.30 ETD00924   30 nM 0.440.54   10 nM 0.47   3 nM 0.52   1 nM 0.63  0.3 nM 0.82  0.1 nM 0.91 0.03nM 0.99 ETD00925   3 nM 0.21 ND   1 nM 0.69  0.3 nM 0.99  0.1 nM 0.870.03 nM 0.88 ETD00926   3 nM 0.46 0.91   1 nM 0.84  0.3 nM 1.09  0.1 nM1.21 0.03 nM 1.46 ETD00928   30 nM 0.56 0.13   10 nM 0.47   3 nM 0.49  1 nM 0.55  0.3 nM 0.76  0.1 nM 1.45 0.03 nM 1.55 ETD00930   3 nM 0.70ND   1 nM 0.76  0.3 nM 0.95  0.1 nM 0.90 0.03 nM 1.07 ETD00931   3 nM0.29 ND   1 nM 0.77  0.3 nM 0.88  0.1 nM 0.97 0.03 nM 0.92 ETD00933   30nM 0.26 0.13   10 nM 0.26   3 nM 0.28   1 nM 0.29  0.3 nM 0.37  0.1 nM0.67 0.03 nM 0.71 ETD00934   3 nM 0.53 ND   1 nM 0.66  0.3 nM 0.65  0.1nM 0.97 0.03 nM 0.98 “—” untreated U-138 MG cells; ND, Not Determined

Some siRNAs having sense strands in accordance with SEQ ID NOs:13974-13977, and having antisense strands in accordance with SEQ ID NOs:13982-13985, were synthesized with an alternative modification patternand are included in Table 8. The siRNAs in Table 8 were based, at leastpartially, on siRNAs having sense strand sequences comprising thesequences of SEQ ID NOs: 759, 1285, 1580, and 1840, and having antisensestrand sequences comprising the sequences of SEQ ID NOs: 2613, 3139,3434, and 3694.

TABLE 8 Alternative Modification Patterns of Select siRNAs Sense strandAntisense strand ETD# sequence (5′-3′) sequence (5′-3′) ETD01062csasgaGfuGfgAfcu usUfsucaAfauaguc auuugaaasusu cAfcUfcugsusu ETD01063asgscuUfaAfgAfag usAfsgauUfcccuuc ggaaucuasusu uUfaAfgcususu ETD01064gsasucGfaGfgCfug usUfsaucCfugcagc caggauaasusu cUfcGfaucsusu ETD01065csasgaGfuUfcUfug usUfsuuaUfuccaag gaauaaaasusu aAfcUfcugsusuSense strand - Antisense strand - ETD# SEQ ID NO: SEQ ID NO: ETD0106213986 14134 ETD01063 13987 14135 ETD01064 13988 14136 ETD01065 1398914137

IC50 values for knockdown of ANGPTL4 mRNA for ETD01062, ETD01063,ETD01064 and ETD01065 ANGPTL4 siRNAs were determined in U-138 MG cells.The siRNAs were assayed individually at 30 nM, 10 nM, 3 nM, 1 nM, 0.3nM, 0.1 nM and 0.03 nM. The U-138 MG (ATCC® HTB-16) cells were seeded in96-well tissue culture plates at a cell density of 7,500 cells per wellin EMEM (BD Biosciences Catalog No. 670086) supplemented with 10% fetalbovine serum and incubated overnight in a water-jacketed, humidifiedincubator at 37° C. in an atmosphere composed of air plus 5% carbondioxide. The ANGPTL4 siRNAs were individually transfected into U-138 MGcells in triplicate wells using 0.3 μL Lipofectamine RNAiMax (Fisher)per well. After incubation for 48 hours at 37° C., total RNA washarvested from each well and cDNA prepared using TaqMan® Fast AdvancedCells-to-CT™ Kit (ThermoFisher, Catalog #A35374) according to themanufacturer's instructions. The level of ANGPTL4 mRNA from each wellwas measured in triplicate by real-time qPCR on an Applied Biosystems7500 Fast Real-Time PCR machine using TaqMan Gene Expression Assay forhuman ANGPTL4 (ThermoFisher, assay #Hs01101127_m1). The level of PPIAmRNA was measured using TaqMan Gene Expression Assay (ThermoFisher,assay #Hs99999904_m1) and used to determine relative ANGPTL4 mRNA levelsin each well using the delta-delta Ct method. All data were normalizedto relative ANGPTL4 mRNA levels in untreated U-138 MG cells. Curve fitwas accomplished using the [inhibitor] vs. response (three parameters)function in GraphPad Prism software. Results are shown in Table 9.

TABLE 9 IC50 Values of ETD01062, ETD01063, ETD01064 and ETD01065 ANGPTL4siRNAs in Human U-138 MG Cells Relative ANGPTL4 siRNA [siRNA] mRNALevels IC50 (nM) — — 1   ND ETD01062   30 nM 0.41 0.22   10 nM 0.39   3nM 0.36   1 nM 0.42  0.3 nM 0.63  0.1 nM 0.70 0.03 nM 0.82 ETD01063   30nM 0.68 1.24   10 nM 0.62   3 nM 0.62   1 nM 0.71  0.3 nM 1.54  0.1 nM1.15 0.03 nM 0.89 ETD01064   30 nM 0.83 0.25   10 nM 0.41   3 nM 0.57  1 nM 0.57  0.3 nM 0.71  0.1 nM 1.27 0.03 nM 0.89 ETD01065   30 nM 0.240.07   10 nM 0.23   3 nM 0.20   1 nM 0.27  0.3 nM 0.31  0.1 nM 0.42 0.03nM 0.56 “—” untreated U-138 MG cells; ND, Not Determined

Example 6: Assessing the Extent of Nuclease Resistance of ANGPTL4 siRNAs

Resistance of select ANGPTL4 siRNAs to nuclease digestion was assessedby incubating the siRNAs in rat liver tritosomes. Each siRNA (7 ng/μLfinal concentration) was placed into a PCR tube containing a cocktailprepared on ice containing 1× catabolic buffer (Xenotech, Catalog#K5200, Lot #18-1-0698), 0.5× rat tritosomes (Xenotech, Catalog#R0610.LT, Lot #1610405), 0.1 U/4 porcine intestinal heparin (Zageno,Catalog #H3149-10KU). An aliquot was removed, an equal volume of 50 mMEDTA was added, and the sample placed at −80° C. This sample wasdesignated as the 0 hr timepoint. The remainder of the reaction wasplaced in an Eppendorf Mastercycler Gradient and incubated at 37° C.After incubation for 4 and 24 hours, an aliquot was removed from thereaction and stopped by addition of an equal volume of 50 mM EDTA andplaced at −80° C. until analysis by gel electrophoresis. All sampleswere then thawed on ice and 6×DNA Gel Loading Dye (ThermoFisher Catalog#R0611) was added to 1× final concentration. 20 μL of each sample wasloaded onto a 20% polyacrylamide TBE gel (ThermoFisher, Catalog#EC63155BOX). Electrophoresis was carried out at a constant 100V for 75minutes in an XCell SureLock Mini-Cell Electrophoresis System(ThermoFisher) using 1× TBE (Tris/boric/EDTA) (Fisher, Catalog #FERB52)as the tank buffer. The siRNA was visualized by staining the gel with a1:10,000 dilution of SYBR Gold (ThermoFisher, Catalog #S-11494) in TBEfor 15 minutes at room temperature with rocking. The gel was washed with1× TBE for 15 minutes and then placed on a FotoPrep1 UV transilluminator(Fotodyne). The gel was imaged using the camera app set on MONO on aniPhone 6s with a yellow gel filter (Neewer) placed over the lens. Bandintensity was measured using NIH ImageJ using the “Analyze: Gels”function. The remaining siRNA percent was normalized to the valueobtained at the 0 hr timepoint for that siRNA. Results are shown inTable 10. By using this assay, we were able to determine that somesiRNAs are more resistant to nuclease digestion with more remainingintact over time compared with other siRNAs with the same modificationpattern.

TABLE 10 Resistance of ANGPTL4 siRNAs to Nucleases Present in Rat LiverTritosomes % siRNA Timepoint (hr) remaining ETD00686 0 100% 4  79% 24 27% ETD00714 0 100% 4  66% 24  33% ETD00721 0 100% 4  77% 24  47%ETD00728 0 100% 4  74% 24  32% ETD00736 0 100% 4  81% 24  39% ETD00916 0100% 4  85% 24  59% ETD00924 0 100% 4  68% 24  24% ETD00926 0 100% 4 74% 24  47% ETD00928 0 100% 4  73% 24  25% ETD00933 0 100% 4  73% 24 28%

Example 7: Screening ANGPTL4 ASOs for Activity in Cells in Culture

ANGPTL4 ASOs with sequences provided in SEQ ID NOs: 3709-13934 and thosepossessing modification pattern ASO1 (SEQ ID NO: 13969) are to beassayed for ANGPTL4 mRNA reduction activity in cells in culture. A cellline such as ARPE-19 that expresses ANGPTL4 (ATCC® CRL-2302) will beseeded in 96-well tissue culture plates at a cell density of 10,000cells per well in DMEM supplemented with 10% fetal bovine serum andincubated overnight in a water-jacketed, humidified incubator at 37° C.in an atmosphere of air plus 5% carbon dioxide. The ANGPTL4 ASOs areindividually transfected into cells in duplicate wells at 1 uM finalconcentration using 0.3 uL Lipofectamine RNAiMax (Fisher) per well. Anegative control ASO (SEQ ID NO: 13953) is also transfected at 1 uMfinal concentration. After incubation for 48 hours at 37° C., total RNAis harvested from each well and cDNA prepared using TaqMan® FastAdvanced Cells-to-CT™ Kit (ThermoFisher, Catalog #A35374) according tothe manufacturer's instructions. The level of ANGPTL4 mRNA from eachwell will be measured in triplicate by real-time qPCR on an AppliedBiosystems 7500 Fast Real-Time PCR machine using TaqMan Gene ExpressionAssay for human ANGPTL4 (ThermoFisher, assay #Hs01101127_m1). The levelof PPIA mRNA is measured using TaqMan Gene Expression Assay(ThermoFisher, assay #Hs99999904_m1) and used to determine relativeANGPTL4 mRNA levels in each well using the delta-delta Ct method. Dataare normalized to relative ANGPTL4 mRNA levels in untreated ARPE-19cells.

The ANGPTL4 ASOs showing the greatest degree of reduction of ANGPTL4mRNA at 1 uM are to be tested in a second screen for activity at 100 nMconcentration using the transfection procedures as described above.

Example 8: GalNAc Ligand for Hepatocyte Targeting of Oligonucleotides

Without limiting the disclosure to these individual methods, there areat least two general methods for attachment of multivalentN-acetylgalactosamine (GalNAc) ligands to oligonucleotides: solid orsolution-phase conjugations. GalNAc ligands may be attached to solidphase resin for 3′ conjugation or at the 5′ terminus using GalNAcphosphoramidite reagents. GalNAc phosphoramidites may be coupled onsolid phase as for other nucleosides in the oligonucleotide sequence atany position in the sequence. Reagents for GalNAc conjugation tooligonucleotides are shown in Table 11.

TABLE 11 GalNAc Conjugation Reagents Type of conjugation Structure Solidphase 3’ attachment where squiggly line is rest of oligonucleotide chainand right- most OH is where attachment′ to solid phase is.

Solid phase 5’ attachment phosphoramidite

Solid phase 5’ attachment Phosphoramidite

Solution phase Carboxylic acid for amide coupling anywhere onoligonucleotide

In solution phase conjugation, the oligonucleotide sequence—including areactive conjugation site—is formed on the resin. The oligonucleotide isthen removed from the resin and GalNAc is conjugated to the reactivesite.

The carboxy GalNAc derivatives may be coupled to amino-modifiedoligonucleotides. The peptide coupling conditions are known to theskilled in the art using a carbodiimide coupling agent like DCC(N,N′-Dicyclohexylcarbodiimide), EDC(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide) or EDC.HCl(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and anadditive like HOBt (1-hydroxybenztriazole), HOSu (N-hydroxysuccinimide),TBTU (N,N,N,N-Tetramethyl-O-(benzotriazol-1-yl)uroniumtetrafluoroborate, HBTU(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) or HOAt (1-Hydroxy-7-azabenzotriazole and commoncombinations thereof such as TBTU/HOBt or HBTU/HOAt to form activatedamine-reactive esters.

Amine groups may be incorporated into oligonucleotides using a number ofknown, commercially available reagents at the 5′ terminus, 3′ terminusor anywhere in between.

Non-limiting examples of reagents for oligonucleotide synthesis toincorporate an amino group include:

-   -   5′ attachment:    -   6-(4-Monomethoxytritylamino)hexyl-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite        CAS Number: 114616-27-2    -   5′-Amino-Modifier TEG CE-Phosphoramidite    -   10-(O-trifluoroacetamido-N-ethyl)-triethyleneglycol-1-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite    -   3′ attachment:    -   3′-Amino-Modifier Serinol CPG    -   3-Dimethoxytrityloxy-2-(3-(fluorenylmethoxycarbonylamino)propanamido)propyl-1-O-succinyl-long        chain alkylamino-CPG (where CPG stands for controlled-pore glass        and is the solid support)    -   Amino-Modifier Serinol Phosphoramidite    -   3-Dimethoxytrityloxy-2-(3-(fluorenylmethoxycarbonylamino)propanamido)propyl-1-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite

Internal (base modified):

-   -   Amino-Modifier C6 dT    -   5′-Dimethoxytrityl-5-[N-(trifluoroacetylaminohexyl)-3-acrylimido]-2′-deoxyUridine,3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite.        CAS Number: 178925-21-8

Solution phase conjugations may occur after oligonucleotide synthesisvia reactions between non-nucleosidic nucleophilic functional groupsthat are attached to the oligonucleotide and electrophilic GalNAcreagents. Examples of nucleophilic groups include amines and thiols, andexamples of electrophilic reagents include activated esters (e.g.N-hydroxysuccinimide, pentafluorophenyl) and maleimides.

Example 9: Inhibition of ANGPTL4 in a Mouse Model ofHypertriglyceridemia

In this experiment, a murine model of hypertriglyceridemia is to be usedto evaluate the effect of siRNA or ASO inhibition of ANGPTL4 expressedin the liver compared to an anti-mouse ANGPTL4 antibody. The mousestrain C57Bl/6 Apoetm1Unc mice (Jackson Labs) will be maintained on ahigh fat Western diet (Research Diets, D12492; 60% fat by calories).

Four groups of mice (n=12/group) will be utilized in this study. Animalswill be maintained on a high fat diet during the study. On Day −4 beforethe first injection, chow will be removed for an overnight fast. On Day−3 before the first injection, all animals will be anesthetized and 300uL of blood collected in serum separator tubes via the submandibularvein to assess baseline triglyceride, serum glucose, insulinsensitivity, total cholesterol levels, HDL Cholesterol levels, liverfunction and serum levels of ANGPTL4 protein. On Study Day 0, Group 1mice will be injected intraperitoneally with 600 uL normal saline, Group2 mice will be injected intraperitoneally with 600 ug of anti-mouseANGPTL4 antibody in 600 uL, Group 3 mice will be injected subcutaneouslywith 100 ug of GalNAc-ANGPTL4 siRNA targeting mouse ANGPTL4 with sensestrand selected from sequences provided in SEQ ID NO: 13937-13944,14289, or 14291, and antisense strands selected from sequences providedin SEQ ID NO: 13945-13952, 14290, or 14292, in 200 uL of normal saline,and Group 4 mice will be injected subcutaneously with 150 ug ofGalNAc-ANGPTL4 ASO targeting mouse ANGPTL4 in 200 uL of normal saline.The sense strands selected from sequences provided in SEQ ID NO:13937-13944, 14289, or 14291 will comprise a GalNAc ligand attached tothe 3′ end of the sense strands. On the afternoon of Day 3, the chowwill be removed from all Groups for an overnight fast. On Day 4, theanimals from all Groups will be anesthetized and 150 uL of bloodcollected in serum separator tubes via the submandibular vein to assessserum triglycerides, glucose, total cholesterol, HDL cholesterol andlevels of ANGPTL4 protein. Animals from all groups will then undergo anoral glucose tolerance test and insulin tolerance test to evaluateinsulin sensitivity. Chow will be supplied again as normal after bloodhas been collected and insulin sensitivity tests conducted. Weeklythereafter starting on Day 7 the animals from Group 2 will be dosed ason Day 0 for a total of 15 injections. Every other week thereafterstarting on Day 14 the animals from Group 3 and Group 4 will be dosed ason Day 0 for a total of 8 injections. Every other week starting on Day10, the mice from all Groups will be fasted (overnight) and bled (150 uLinto serum separator tubes) to assess serum triglyceride, glucose, totalcholesterol, HDL cholesterol and levels of ANGPTL4 protein, and undergoinsulin sensitivity tests. On the third day after the final injection,the chow will be removed from all Groups for an overnight fast. On thefourth day after the final injection, the animals from all Groups willbe anesthetized, euthanized and bled via cardiac puncture to collect 500uL of blood into serum separator tubes to assess triglyceride, serumglucose, insulin sensitivity, total cholesterol levels, HDL cholesterollevels, liver function and serum levels of ANGPTL4 protein. Tissue fromthe liver, small intestine and mesenteric lymph nodes will be collectedfrom all animals and immersed in 10% neutral buffered formalin forhistopathological analysis. A liver sample will also be collected fromall animals and placed in RNAlater. The levels of ANGPTL4 mRNA will beassessed by RT-qPCR using TaqMan assays for mouse ANGPTL4 (ThermoFisher,assay #Mm00480431_m1) and the mouse housekeeping gene PPIA(ThermoFisher, assay #Mm02342430_g1).

Animals treated with the anti-mouse ANGPTL4 antibody (Group 2), micetreated with GalNAc-ANGPTL4 siRNA (Group 3), and mice treated withGalNAc-ANGPTL4 ASO (Group 4) are expected to have decreasedtriglycerides, total serum cholesterol, serum glucose as well asdecreased serum ANGPTL4 protein levels, and increased HDL cholesteroland insulin sensitivity, compared with mice from Group 1 (saline).Animals in Group 2 and Group 3 are also expected to have decreasedANGPTL4 mRNA in liver samples.

Example 10: Inhibition of ANGPTL4 in Non-Human Primates UsingGalNAc-ANGPTL4 siRNA and GalNAc-ANGPTL4 ASO

In this experiment, a NHP model of hypertriglyceridemia is used toevaluate the effect of siRNA or ASO inhibition of ANGPTL4 expressed inthe liver. Three groups of cynomolgus monkeys will be used (n=5/group)that are placed on a high-fat diet (Western Primate Diet, 5S2T) beforethe initiation of the study. Alternatively, three groups of rhesusmonkeys will be used (n=5/group) that are placed on a high fructose dietbefore the initiation of the study. Animals are to be given 7 biweeklysubcutaneous injections of saline (Group 1), GalNAc-ANGPTL4 siRNA (Group2), or GalNAc-ANGPTL4 ASO (Group 3). The modified GalNAc-ANGPTL4 siRNAsequences are chosen from subset A that are cross-reactive between humanand NHP, and include modification pattern 1S, 2S or 3S and 1AS or 3AS.Other GalNAc-ANGPTL4 siRNA sequences may be chosen from subset F thatare cross-reactive between human and NHP, or modifications thereof.Blood samples for lipid and glycemic measurements will be collected atbaseline and at 4, 8, and 14 weeks of the study and analyzed for lipidcontent, serum glucose, insulin sensitivity and ANGPTL4 protein. Allanimals from each group are necropsied 2 weeks after the last bloodcollection. Tissue from the liver, small intestine and mesenteric lymphnodes will be collected from all animals and immersed in 10% neutralbuffered formalin for histopathological analysis. A liver sample willalso be collected from all animals and placed in RNAlater. The levels ofANGPTL4 mRNA will be assessed by RT-qPCR using TaqMan assays forcynomolgus ANGPTL4 (ThermoFisher, assay #Mf01101127_m1) or rhesusANGPTL4, and the cynomolgus housekeeping gene PPIA (ThermoFisher, assay#Mf04932064_gH) or rhesus PPIA.

It is expected that animals treated with the GalNAc ANGPTL4 siRNA (Group2) and animals treated with GalNAc-ANGPTL4 ASO (Group 3) will showdecreased triglycerides, total serum cholesterol and serum glucose aswell as decreased serum ANGPTL4 protein levels, and increased HDLcholesterol and insulin sensitivity, compared with animals from Group 1(saline). It is also expected that animals in Group 1 and Group 3 willshow decreased ANGPTL4 mRNA in liver samples.

Example 11: Inhibition of ANGPTL4 in a Clinical Trial UsingGalNAc-ANGPTL4 siRNA and GalNAc-ANGPTL4 ASO

In this study, human subjects with hypertriglyceridemia are used toevaluate the effect of siRNA or ASO inhibition of ANGPTL4 expressed inthe liver. Selection criteria for inclusion in the study are ages 40-90,BMI≥30, and serum triglycerides≥250 mg/dL. Three groups of subjects willbe included (n=15/group) in the study. Subjects are to be given 5 weeklysubcutaneous injections of saline (Group 1), GalNAc-ANGPTL4 siRNA (Group2), or GalNAc-ANGPTL4 ASO (Group 3). The modified GalNAc-ANGPTL4 siRNAsequences are chosen from subset A that show high activity in cells inculture in the experiments of Example 4. Blood samples for lipid andglycemic measurements will be collected at baseline and at 3, 6, and 12weeks of the study and analyzed for lipid content, serum glucose,insulin sensitivity, ANGPTL4 protein, and liver and kidney function.

It is expected that subjects treated with the GalNAc ANGPTL4 siRNA(Group 2) and subjects treated with GalNAc-ANGPTL4 ASO (Group 3) willshow decreased triglycerides, total serum cholesterol and serum glucoseas well as decreased serum ANGPTL4 protein levels, and increased HDLcholesterol and insulin sensitivity, compared with subjects from Group 1(saline).

Example 12: siRNA-Mediated Knockdown of ANGPTL4 in a Mouse Model ofHypertriglyceridemia

The effects of siRNA-mediated knockdown of ANGPTL4 in the liver wasinvestigated in a murine model of hypertriglyceridemia. Eight- toten-week-old C57Bl/6 Apoetm1Unc mice (Jackson Labs) were placed on ahigh fat Western diet (Research Diets, D12492; 60% fat by calories) fortwo weeks prior to the start of the study on Day 0. On Day 0 and Day 7,mice in Group 1 (n=4) were given 200 uL of phosphate buffered saline(PBS) and mice in Group 2 (n=4) were given 200 ug of the siRNA targetingmouse ANGPTL4 (ETD00642: sense strand having the sequence of SEQ ID NO:13941 and a 3′ conjugated GalNAc ligand, and antisense strand having thesequence of SEQ ID NO: 13949) in 200 uL PBS by subcutaneous injection.Serum samples were collected from all mice fed ad libidum on Day 13. OnDay 14, serum samples were collected from all mice after a 24 hour fast.Clinical chemistry assays including those for triglyceride and glucosewere performed at IDEXX Laboratories, Incorporated. All mice were theneuthanized and a liver sample from each was collected and placed inRNAlater (ThermoFisher Cat #AM7020). Total liver RNA was prepared byhomogenizing the liver tissue in homogenization buffer (Maxwell RSCsimplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (BertinInstruments) set at 5000 rpm for two 10 second cycles. Total RNA fromthe lysate was purified on a Maxwell RSC 48 platform (PromegaCorporation) according to the manufacturer's recommendations. The levelsof liver ANGPTL4 mRNA were assessed by RT-qPCR using TaqMan assays formouse ANGPTL4 (ThermoFisher, assay #Mm00480431_m1) and the mousehousekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1). Data werenormalized to the level in animals receiving PBS (Group 1). Results areshown in Table 12. Mice receiving ETD00642 (Group2) had reduced levelsof liver ANGPTL4 mRNA compared to mice receiving PBS (Group 1).

TABLE 12 Day 14 ANGPTL4 mRNA Levels in Mice Treated with ETD00642Relative Liver Mean Relative ANGPTL4 Liver ANGPTL4 Group # Animal # mRNALevel mRNA level 1 1 1.30 1.00 2 0.95 3 1.11 4 0.73 2 5 0.48 0.47 6 0.557 0.51 8 0.36

The levels of triglycerides and glucose are shown in Table 13. The serumtriglyceride levels in fed mice on Day 13 and fasted mice on Day 14 werelower in mice receiving ETD00642 (Group 2) than in control micereceiving PBS (Group1). The serum glucose levels in fed mice on Day 13were lower in mice receiving ETD00642 (Group 2) than in control micereceiving PBS (Group1). The serum glucose levels in fasted mice on Day14 were also lower in mice receiving ETD00642 (Group 2) than in controlmice receiving PBS (Group1), but the difference between Groups was lessthan that in the fasted mice.

TABLE 13 Triglyceride and Glucose Levels in Mice Treated with ETD00642Triglycerides (mg/dL) Glucose (mg/dL) Group Animal Fed (Day 13) Fasted(Day 14)  Fed (Day 13) Fasted (Day 14) # # individual Mean individualMean individual Mean individual Mean 1 1 180 201 119 117 297 296 129 1032 213 135 300 110 3 193  99 305  91 4 217 113 280  80 2 5 148 140  65 69 210 202  97  89 6 158  66 218 100 7  66  61 221  76 8 186  85 158 83

Example 13: Activity of siRNAs Targeting ANGPTL4 in Non-Human Primates

The activity of four siRNAs targeting ANGPTL4 were tested individuallyin cynomolgus monkeys. The siRNAs utilized in this study includedETD01117, ETD01118, ETD01119, and ETD01120 (see Table 16 for siRNAdetails).

Female cynomolgus monkeys (Macaca fascicularis, Cambodian origin, OrientBioResource Center, Alice, Tex.) were at least 18 months of age andweighed 2.5-3 kg at study start. After arrival, the animals were pairhoused in stainless steel cages suspended over flush pans. Fluorescentlighting on a 12 hour on/off cycle was used and the temperaturemaintained at 18-29□ C. at a target relative humidity of 30-70% with atleast 10-15 air exchanges per hour. Animals were acclimated for a periodof at least twenty-eight days, during which time they were examined foroverall general health and observed daily. Animals were limit fed dailywith certified primate diet (5048). Tap water was provided ad libitum.

Monkeys (3/group) were administered the siRNA test article once on Day 0by subcutaneous injection as described in Table 14. In-life, animalswere evaluated for clinical signs of toxicity, body weights, and foodconsumption. Prior to and during the study evaluations for clinicalchemistry parameters were performed.

TABLE 14 siRNA Dosing Information Dosage Conc. Animal Group siRNA(mg/kg) (mg/mL) No. 1 ETD01117 5 50 1-3 2 ETD01118 5 50 4-6 3 ETD01119 550 7-9 4 ETD01120 5 50 10-12

Whole blood (approximately 2-3 mL) was collected from fasted animalstwice prior to first dose (Day −7 and −2), and from surviving animals onDays 7, 14. Whole blood (approximately 2-3 mL) was collected fromnon-fasted animals once prior to dosing (Day −8). Blood samples wereanalyzed for clinical chemistry parameters, processed to serum formeasurement of ANGPTL4 levels, and processed to plasma for lipoproteinprofile assay.

An AlphaLISA immunoassay (PerkinElmer AL3017) was used to measure serumANGPTL4 levels according to the recommended protocols provided by themanufacturer. Briefly, standard analyte (recombinant human ANGPTL4encoding residues Gly26-Ser406) and serum samples were prepared in 1×AlphaLISA Assay Buffer (PerkinElmer AL000C). For each assay, 5 μL ofprepared standard analyte or diluted sample were added to a 96-wellwhite ½ Area OptiPlate (PerkinElmer 6002290) followed by the addition of10 μL of Acceptor bead mix. Then the plate was sealed with TopSealA-PLUS (PerkinElmer 6050185) and incubated for 30 minutes at roomtemperature. Next, 10 μL of biotinylated antibody was added to each wellof the plate. The plate was sealed and incubated for 60 minutes at roomtemperature. Afterwards, 25 μL of streptavidin Donor beads were added inthe dark to prevent photobleaching. The plate was sealed, covered withfoil, and incubated at room temperature for 30 minutes prior tomeasuring AlphaLISA signal. All Alpha assays were measured on theAlpha-enabled EnVision multilabel plate reader using the 640 as mirrormodule (#444) and the M570w emission filter (#244). Standard Alphameasurement settings were used: excitation wavelength at 680 nm was usedto excite Donor beads and emission wavelength at 615 nm measured asAlpha signal; total measurement time 550 ms and excitation time 180 mswere used. A standard curve was generated by plotting the Alpha signalcounts versus the concentration of analyte using GraphPad Prism version9 for macOS (GraphPad Software). The curve was fit according to anonlinear regression using the 4-parameter logistic equation (sigmoidaldose-response curve with variable slope) and a 1/Y2 data weighting.Signal for samples was converted to pg/mL from interpolation of thestandard curve from each plate and corrected for dilution of sampleprior to assay. The results are shown in Table 15. Results indicate thatafter treatment with siRNAs targeting ANGPTL4 the mean levels of ANGPTL4protein in serum were reduced. In addition, mean levels of serum ANGPTL4protein levels were lower in fed animals than in fasted animals.

TABLE 15 Serum ANGPTL4 Protein Levels in Non-Human Primates Treated withANGPTL4 siRNAs Group # Group (n = 3) siRNA Day Means* 1 ETD01117 −8(fed) 0.66 −7 0.97 −2 1.03 7 0.66 14 0.38 2 ETD01118 −8 (fed) 0.68 −71.10 −2 0.90 7 0.61 14 0.68 3 ETD01119 −8 (fed) 0.73 −7 1.07 −2 0.93 70.50 14 0.65 4 ETD01120 −8 (fed) 0.49 −7 0.94 −2 1.06 7 0.52 14 0.52*relative to the mean of Day −7 and Day −2 values in each group

Example 14: siRNAs Targeting ANGPTL4

Some non-limiting examples of siRNAs have one or more characteristics ofthe siRNAs in Table 16.

TABLE 16 Exemplary modified siRNAs Sense Antisense Strand AdditionalStrand siRNA Sequence - Characteristic Sequence - Name SEQ ID NO:of Sense Strand SEQ ID NO: ETD01062 13986 — 14134 ETD01063 13987 — 14135ETD01064 13988 — 14136 ETD01065 13989 — 14137 ETD01117 13990GalNAc#23 conjugated 14134 at 3′ end ETD01118 13991 GalNAc#23 conjugated14135 at 3′ end ETD01119 13992 GalNAc#23 conjugated 14136 at 3′ endETD01120 13993 GalNAc#23 conjugated 14137 at 3′ end ETD01117.1 13994GalNAc ligand 14134 conjugated at 5′ end ETD01118.1 13995 GalNAc ligand14135 conjugated at 5′ end ETD01119.1 13996 GalNAc ligand 14136conjugated at 5′ end ETD01120.1 13997 GalNAc ligand 14137conjugated at 5′ end ETD01117.2 13998 GalNAc ligand 14134conjugated at 5′ end ETD01118.2 13999 GalNAc ligand 14135conjugated at 5′ end ETD01119.2 14000 GalNAc ligand 14136conjugated at 5′ end ETD01120.2 14001 GalNAc ligand 14137conjugated at 5′ end ETD01117.3 14006 GalNAc ligand 14138conjugated at 5′ end ETD01118.3 14007 GalNAc ligand 14139conjugated at 5′ end ETD01119.3 14008 GalNAc ligand 14140conjugated at 5′ end ETD01120.3 14009 GalNAc ligand 14141conjugated at 5′ end ETD01117.4 14006 GalNAc ligand 14142conjugated at 5′ end ETD01118.4 14007 GalNAc ligand 14143conjugated at 5′ end ETD01119.4 14008 GalNAc ligand 14144conjugated at 5′ end ETD01120.4 14009 GalNAc ligand 14145conjugated at 5′ end ETD01117.5 14006 GalNAc ligand 14146conjugated at 5′ end ETD01118.5 14007 GalNAc ligand 14147conjugated at 5′ end ETD01119.5 14008 GalNAc ligand 14148conjugated at 5′ end ETD01120.5 14009 GalNAc ligand 14149conjugated at 5′ end ETD01117.6 14006 GalNAc ligand 14150conjugated at 5′ end ETD01118.6 14007 GalNAc ligand 14151conjugated at 5′ end ETD01119.6 14008 GalNAc ligand 14152conjugated at 5′ end ETD01120.6 14009 GalNAc ligand 14153conjugated at 5′ end ETD01117.7 14002 GalNAc ligand 14154conjugated at 5′ end ETD01118.7 14003 GalNAc ligand 14155conjugated at 5′ end ETD01119.7 14004 GalNAc ligand 14156conjugated at 5′ end ETD01120.7 14005 GalNAc ligand 14157conjugated at 5′ end

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

We claim:
 1. A composition comprising an oligonucleotide that targetsAngiopoietin like 4 (ANGPTL4) and when administered to a cell decreasesexpression of ANGPTL4; wherein the oligonucleotide comprises a smallinterfering RNA (siRNA) comprising a sense strand and an antisensestrand, wherein the sense strand comprises an oligonucleotide sequenceof any of SEQ ID NOS: 13971-13973 or 13975-13977 in which at least oneinternucleoside linkage is modified and at least one nucleoside ismodified, or an oligonucleotide sequence comprising 1 or 2 nucleosidesubstitutions, additions, or deletions of any of 13971-13973 or13975-13977 in which at least one internucleoside linkage is modifiedand at least one nucleoside is modified; and wherein the antisensestrand comprises an oligonucleotide sequence of any of SEQ ID NOS:13979-13981 or 13983-13985 in which at least one internucleoside linkageis modified and at least one nucleoside is modified, or anoligonucleotide sequence comprising 1 or 2 nucleoside substitutions,additions, or deletions of any of SEQ ID NOS: 13979-13981 or 13983-13985in which at least one internucleoside linkage is modified and at leastone nucleoside is modified.
 2. The composition of claim 1, wherein theat least one nucleoside is modified comprises a 2′-fluoro modifiednucleoside.
 3. The composition of claim 1, wherein the at least onenucleoside is modified comprises a 2′-O-methyl modified nucleoside. 4.The composition of claim 1, wherein the oligonucleotide comprises 15-23modified nucleosides.
 5. The composition of claim 4, wherein the 15-23modified nucleosides comprises 2′-fluoro modified nucleosides and2′-O-methyl modified nucleosides.
 6. The composition of claim 1, whereinthe at least one internucleoside linkage is modified comprises aphosphorothioate linkage.
 7. The composition of claim 1, wherein theoligonucleotide comprises a GalNAc ligand attached to theoligonucleotide.
 8. The composition of claim 7, wherein the GalNAcligand comprises 3 GalNAc moieties.
 9. The composition of claim 7,wherein the GalNAc ligand attached to the oligonucleotide comprises aGalNAc ligand attached at a 5′ or 3′ terminus of the sense strand. 10.The composition of claim 1, wherein the antisense strand comprises thenucleoside sequence of any of SEQ ID NOS: 13979-13981 or 13983-13985,and wherein the sense strand comprises the nucleoside sequence of any ofSEQ ID NOS: 13971-13973 or 13975-13977.
 11. The composition of claim 1,wherein the sense strand or the antisense strand comprises a 3′overhang.
 12. A composition comprising an oligonucleotide that targetsAngiopoietin like 4 (ANGPTL4) and when administered to a cell decreasesexpression of ANGPTL4; wherein the oligonucleotide comprises a smallinterfering RNA (siRNA) comprising a sense strand and an antisensestrand, wherein the sense strand comprises an oligonucleotide sequenceof any of SEQ ID NOS: 13970-13977 in which at least one internucleosidelinkage is modified and at least one nucleoside is modified, or anoligonucleotide sequence comprising 1 or 2 nucleoside substitutions,additions, or deletions of any of SEQ ID NOS: 13970-13977 in which atleast one internucleoside linkage is modified and at least onenucleoside is modified; wherein the antisense strand comprises anoligonucleotide sequence of any of SEQ ID NOS: 13978-13985 in which atleast one internucleoside linkage is modified and at least onenucleoside is modified, or an oligonucleotide sequence comprising 1 or 2nucleoside substitutions, additions, or deletions of any of SEQ ID NOS:13978-13985 in which at least one internucleoside linkage is modifiedand at least one nucleoside is modified; and wherein the sense strand orthe antisense strand comprises one of the following modificationpatterns: 5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13954),5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13955),5′-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13956),5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3′ (SEQ ID NO: 13957),5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3′ (SEQ ID NO: 13958),5′-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13959),5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13960),5′-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13961),5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13962),5′-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13963),5′-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13964),5′-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13965),5′-nsNfsnNfnNfnNfNfnnnnNfnNfnnnsnsn-3′ (SEQ ID NO: 13966),5′-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3′ (SEQ ID NO: 13967), or5′-nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13968), wherein “N”comprises one or more nucleosides, “Nf” is a 2′ fluoro-modifiednucleoside, “n” is a 2′ O-methyl modified nucleoside, and “s” is aphosphorothioate linkage.
 13. The composition of claim 1, wherein thesense strand comprises the nucleoside sequence of any of SEQ ID NOS:13973 or a sense strand sequence thereof having 1 or 2 nucleosidesubstitutions, additions, or deletions; and wherein the antisense strandcomprises the nucleoside sequence of SEQ ID NO: 13981 or an antisensestrand sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions.
 14. The composition of claim 1, wherein thesense strand comprises the nucleoside sequence of SEQ ID NO: 13977, andwherein the antisense strand comprises the nucleoside sequence of SEQ IDNO:
 13985. 15. The composition of claim 14, wherein the sense strandcomprises modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′(SEQ ID NO: 13955), and wherein the antisense strand comprisesmodification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′ (SEQ IDNO: 13962), wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. 16.The composition of claim 15, wherein the oligonucleotide comprises aGalNAc ligand attached at a 3′ end of the sense strand.
 17. Thecomposition of claim 14, wherein the sense strand comprises modificationpattern 6S: 5′-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO:13959), wherein “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. 18.The composition of claim 17, wherein the oligonucleotide comprises aGalNAc ligand attached at a 5′ end of the sense strand.
 19. Thecomposition of claim 17, wherein the oligonucleotide comprises a GalNAcligand attached at a 3′ end of the sense strand.
 20. The composition ofclaim 17, wherein the antisense strand comprises modification pattern6AS: 5′-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3′ (SEQ ID NO: 13965), or8AS: 5′-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3′ (SEQ ID NO: 13967), wherein “Nf”is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modifiednucleoside, and “s” is a phosphorothioate linkage.